The Akkadian-speaking people (the earliest historically-attested Semitic-speaking people) who would eventually found Assyria appear to have entered Mesopotamia at some point during the latter 4th millennium BC (c. 3500–3000 BC), eventually intermingling with the earlier Sumerian-speaking population, who came from northern Mesopotamia, with Akkadian names appearing in the written record from as early as the 29th century BC.

During the 3rd millennium BC, a very intimate cultural symbiosis developed between the Sumerians and the Akkadians throughout Mesopotamia, which included widespread bilingualism. The influence of Sumerian (a language isolate) on Akkadian, and vice versa, is evident in all areas, from lexical borrowing on a massive scale, to syntactic, morphological, and phonological convergence. This has prompted scholars to refer to Sumerian and Akkadian in the third millennium BC as a sprachbund. Akkadian gradually replaced Sumerian as the spoken language of Mesopotamia somewhere after the turn of the 3rd and the 2nd millennium BC (the exact dating being a matter of debate), although Sumerian continued to be used as a sacred, ceremonial, literary, and scientific language in Mesopotamia until the 1st century AD, as did the use of the Akkadian cuneiform.

The cities of Assur, Nineveh, Gasur, and Arbela together with a number of other towns and cities, existed since at least before the middle of the 3rd millennium BC (c. 2600 BC), although they appear to have been Sumerian-ruled administrative centers at this time, rather than independent states.

Of the early history of the kingdom of Assyria, little is known. In the Assyrian King List, the earliest king recorded was Tudiya. According to Georges Roux, he would have lived in the mid 25th century BC, i.e. c. 2450 BC. In archaeological reports from Ebla, it appeared that Tudiya's activities were confirmed with the discovery of a tablet where he concluded a treaty for the operation of a karum (trading colony) in the Eblaite territory, with "king" Ibrium of Ebla (who is now known to have been the vizier of Ebla for king Ishar-Damu).

Tudiya was succeeded on the list by Adamu, the first known reference to the Semitic name Adam and then a further thirteen rulers (Yangi, Suhlamu, Harharu, Mandaru, Imsu, Harsu, Didanu, Hanu, Zuabu, Nuabu, Abazu, Belus and Azarah). Nothing concrete is yet known about these names, although it has been noted that a much later Babylonian tablet listing the ancestral lineage of Hammurabi, the Amorite king of Babylon, seems to have copied the same names from Tudiya through Nuabu, though in a heavily corrupted form.

Assyria seems to have already been firmly involved in trade in Asia Minor by this time; the earliest known reference to Anatolian Karu in Hatti was found on later cuneiform tablets describing the early period of the Akkadian Empire (c. 2350 BC). On those tablets, Assyrian traders in Burushanda implored the help of their ruler, Sargon the Great, and this appellation continued to exist throughout the Assyrian Empire for about 1,700 years. The name "Hatti" itself even appears in later accounts of his grandson, Naram-Sin, campaigning in Anatolia.

During the Akkadian Empire (2334–2154 BC), the Assyrians, like all the Akkadian-speaking Mesopotamians (and also the Sumerians), became subject to the dynasty of the city-state of Akkad, centered in central Mesopotamia. The Akkadian Empire founded by Sargon the Great claimed to encompass the surrounding "four-quarters". The region of Assyria, north of the seat of the empire in central Mesopotamia, had also been known as Subartu by the Sumerians, and the name Azuhinum in Akkadian records also seems to refer to Assyria proper. The Sumerians were eventually absorbed into the Akkadian (Assyro-Babylonian) population.

Greco-Roman classical writers such as Julius Africanus, Marcus Velleius Paterculus, and Diodorus Siculus dated the founding of Assyria to various dates between 2284 BC and 2057 BC, listing the earliest king as Belus or Ninus.

The Akkadian Empire was destroyed by economic decline and internal civil war, followed by attacks from barbarian Gutian people in 2154 BC.

Most of Assyria briefly became part of the Neo-Sumerian Empire (or 3rd dynasty of Ur) founded in c. 2112 BC. Sumerian domination extended as far as the city of Ashur but appears not to have reached Nineveh and the far north of Assyria. One local ruler (shakkanakku) named Zāriqum (who does not appear on any Assyrian king list) is listed as paying tribute to Amar-Sin of Ur. Ashur's rulers appear to have remained largely under Sumerian domination until the mid-21st century BC (c. 2050 BC); the king list names Assyrian rulers for this period and several are known from other references to have also borne the title of shakkanakka or vassal governors for the neo-Sumerians.

Ushpia (2080 BC) appears to have been the first fully urbanized independent king of Assyria and is traditionally held to have dedicated temples to the god Ashur in the city of the same name.

In approximately 2025 BC, a king named Puzur-Ashur I came to the throne of Assyria, and there is some debate among scholars as to whether he was the founder of a new dynasty or a descendant of Ushpia. He is mentioned as having conducted building projects in Assur, and he and his successors took the title Išši’ak Aššur (meaning viceroy of Ashur). From this time Assyria began to expand trading colonies called Karum into Hurrian and Hattian lands in Anatolia.

Puzur-Ashur I was succeeded by Shalim-ahum (c. 2000 BC), a king who is attested in a contemporary record of the time, leaving inscriptions in an archaic form of Akkadian.

In addition to the expansions into Anatolia Ilu-shuma (C. 1995–1974 BC) (Middle chronology) appears to have conducted military campaigns in southern Mesopotamia, either in the conquest of the city-states of the south or in order to protect his fellow Akkadian-speakers from incursions by Elamites from the east and/or Amorites from the west – "The freedom of the Akkadians and their children I established. I purified their copper. I established their freedom from the border of the marshes and Ur and Nippur, Awal, and Kismar, Der of the god Ishtaran, as far as Assur".

Ilu-shuma was succeeded by another powerful king, the long-reigning Erishum I (1973–1934 BC) who is notable for one of the earliest examples of written legal codes and introducing the limmu (eponym) lists that were to continue throughout Assyrian history. He is known to have greatly expanded Assyrian trading colonies in Anatolia, with twenty-one being listed during his reign. These Karum traded in: tin, textiles, lapis lazuli, iron, antimony, copper, bronze, wool, and grain, in exchange for gold and silver. Erishum also kept numerous written records and conducted major building works in Assyria, including the building of temples to Ashur, Ishtar, and Adad.

Naram-Sin (1872–1828 BC) repelled an attempted usurpation of his throne by the future king Shamshi-Adad I late in his reign, however, his successor Erishum II was deposed by Shamshi-Adad I in 1809 BC, bringing an end to the dynasty founded either by Ushpia or Puzur-Ashur I.

Shamshi-Adad I (1808–1776 BC) was already the ruler of Terqa, and although he claimed Assyrian ancestry as a descendant of Ushpia, he is regarded as a foreign Amorite usurper by later Assyrian tradition. However, he greatly expanded the Old Assyrian Empire, incorporating the northern half of Mesopotamia, swathes of eastern and southern Anatolia, and much of the Levant into his large empire, and campaigned as far west as the eastern shores of the Mediterranean.

Shamshi-Adad I's son and successor Ishme-Dagan I (1775–1764 BC) gradually lost territory in southern Mesopotamia and the Levant to the state of Mari and Eshnunna respectively and had mixed relations with Hammurabi, the king who had turned the hitherto young and insignificant city-state of Babylon into a major power and empire.

After Shamsi-Adad I's death Assyria was reduced to vassalage by Hammurabi; Mut-Ashkur (1763–1753 BC), Rimush and Asinum were subservient to Hammurabi, who also took ownership of Assyrian trading colonies, thus bringing an end to the Old Assyrian Empire.

However, the Babylonian empire proved to be short-lived, rapidly collapsing after the death of Hammurabi c. 1750 BC. An Assyrian governor named Puzur-Sin deposed Asinum who was regarded as a foreign Amorite and a puppet of the new and ineffectual Babylonian king Sumuabum, and the Babylonian and Amorite presence was expunged from Assyria by Puzur-Sin and his successor Ashur-dugul, who reigned for six years.

A king called Adasi (1720–1701 BC) finally restored strength and stability to Assyria, ending the civil unrest that had followed the ejection of the Babylonians and Amorites, founding the new Adaside Dynasty.

Bel-bani (1700–1691 BC) succeeded Adasi and further strengthened Assyria against potential threats, and remained a revered figure even in the time of Ashurbanipal over a thousand years later.

There followed a long, prosperous and peaceful period in Assyrian history, rulers such as Libaya (1691–1674 BC), Sharma-Adad I, Iptar-Sin, Bazaya, Lullaya, Shu-Ninua, and Sharma-Adad II appear to have had peaceful and largely uneventful reigns.

Assyria remained strong and secure; when Babylon was sacked and its Amorite rulers deposed by the Hittite Empire and subsequently fell to the Kassites in 1595 BC, both powers were unable to make any inroads into Assyria, and there seems to have been no trouble between the first Kassite ruler of Babylon, Agum II, and Erishum III (1598–1586 BC) of Assyria and a mutually beneficial treaty was signed between the two rulers.

Ashur-nadin-ahhe I (1450–1431 BC) was courted by the Egyptians, who were rivals of Mitanni, and attempting to gain a foothold in the Near East. Amenhotep II sent the Assyrian king a tribute of gold to seal an alliance against the Hurri-Mitannian empire. It is likely that this alliance prompted Saushtatar, the emperor of Mitanni, to invade Assyria, and sack the city of Ashur, after which Assyria became a sometime vassal state.

Ashur-nadin-ahhe I was deposed, either by Shaustatar or by his own brother Enlil-nasir II (1430–1425 BC) in 1430 BC, who then paid tribute to Mitanni. Ashur-nirari II (1424–1418 BC) had an uneventful reign and appears to have also paid tribute to the Mitanni Empire.

Ashur-bel-nisheshu (1417–1409 BC) seems to have been independent of Mitannian influence, as evidenced by his signing a mutually beneficial treaty with Karaindash, the Kassite king of Babylonia in the late 15th century. He also undertook extensive rebuilding work in Ashur itself, and Assyria appears to have redeveloped its former highly sophisticated financial and economic systems during his reign.

Ashur-rim-nisheshu (1408–1401 BC) also undertook building work, strengthening the city walls of the capital.

Ashur-nadin-ahhe II (1400–1393 BC) also received a tribute of gold and diplomatic overtures from Egypt, probably in an attempt to gain Assyrian military support against Egypt's Mitannian and Hittite rivals in the region. However, the Assyrian king appears not to have been in a strong enough position to challenge Mitanni or the Hittites.

By the reign of Eriba-Adad I (1392–1366 BC) Mitanni's influence over Assyria was on the wane. Eriba-Adad I became involved in a dynastic battle between Tushratta and his brother Artatama II and after this his son Shuttarna III, who called himself king of the Hurri while seeking support from the Assyrians.

Eriba-Adad I (1392–1366 BC), a son of Ashur-bel-nisheshu, ascended the throne in 1392 BC and finally broke the ties to the Mitanni Empire, and instead turned the tables, and began to exert Assyrian influence on Mitanni.

Ashur-uballit I (1365–1330 BC) went further, defeating Shuttarna III and bringing an end to the Mitanni empire, the Assyrian king then annexing its territories in Anatolia and the Levant, turning Assyria once more into a major empire. The ambitious Assyrian king went further still, attacking and conquering Babylonia, and imposing a puppet ruler loyal to himself upon its throne. Assyria then annexed hitherto Babylonian territory in central Mesopotamia.

Enlil-nirari (1330–1319 BC) also defeated Babylonia's Kassite kings.

Arik-den-ili (1318–1307 BC) campaigned further still, entering northern Ancient Iran and subjugating the 'pre-Iranic' Gutians, Turukku, and Nigimhi, before campaigning deeper into the Levant, subjugating the Suteans, Ahlamu, and Yauru.

Arik-den-ili's successor Adad-nirari I (1307–1275 BC) was another highly successful military leader, he defeated and conquered the Hurro-Mitanni kingdom of Hanigalbat and the rest of the independent Hurro-Mitanni kingdoms of Anatolia, despite the Hittites attempting to support their allies.

Adad-nirari I inflicted a crushing defeat on Babylonia at the Battle of Kār Ištar, annexing large swathes of Babylonian territory. Hittite kings during his reign assumed a placatory attitude towards the Assyrian king.

Shalmaneser I (1274–1245 BC) conquered eight kingdoms in central Anatolia in his first year, and in the next, he defeated a coalition of Hittites, Hurrians, Mitanni, and Ahlamu, annexing yet more territory in Anatolia and the Levant, and retaining Assyrian dominion over Babylonia and the northwest of ancient Iran. Shalmaneser also conducted extensive building work in Assur, Nineveh, and Arbela, and founded the city of Kalhu (the Biblical Calah/Nimrud).

Tukulti-Ninurta I (1244–1207 BC), won a major victory against the Hittites and their king Tudhaliya IV at the Battle of Nihriya and took thousands of prisoners. Rather than being content to simply subjugate Babylonian kings as his predecessors had, he conquered Babylonia directly, taking Kashtiliash IV as a captive and ruled there himself as king for seven years, taking on the old title "King of Sumer and Akkad" first used by Sargon of Akkad. Tukulti-Ninurta I thus became the first Akkadian-speaking native Mesopotamian to rule the state of Babylonia, its founders having been foreign Amorites, succeeded by equally foreign Kassites. Tukulti-Ninurta petitioned the god Shamash before beginning his counteroffensive.

A series of short reigning kings followed, these being Ashur-nadin-apli (1207–1204 BC), Ashur-nirari III (1203–1198 BC), Enlil-kudurri-usur (1197–1193 BC), and Ninurta-apal-Ekur (1192–1190 BC), and there were no significant expansions of the empire during their short tenures, and Babylonia seems to have freed itself from the Assyrian yoke for a time.

Ashur-resh-ishi I (1133–1116 BC) restored the tradition of powerful conquering kings. He campaigned to the east, taking the Zagros region of ancient Iran, and subjugated the Amorites, Ahlamu, and the newly appeared Arameans in the Levant. He also defeated the ambitious Nebuchadnezzar I of Babylonia, annexing Babylonian territory in the process.

Tiglath-pileser I (1115–1074 BC) proved to be a long-reigning and all-conquering ruler, who firmly underlined Assyria's position as the world's leading military power. He was succeeded by Asharid-apal-Ekur who reigned for only a short time.

Ashur-bel-kala (1073–1056 BC) kept the vast empire together, campaigning successfully against Urartu and Phrygia to the north and the Arameans to the west. He maintained friendly relations with Marduk-shapik-zeri of Babylon, however upon the death of that king, he invaded Babylonia and deposed the new ruler Kadašman-Buriaš, appointing Adad-apla-iddina as his vassal in Babylon. He built some of the earliest examples of both Zoological Gardens and Botanical Gardens in Ashur, collecting all manner of animals and plants from his empire, and receiving a collection of exotic animals as tributes from Egypt.

Assyria and its empire were not unduly affected by these tumultuous events for some 150 years, perhaps the only ancient power that was not, and in fact thrived for most of the period. However, upon the death of Ashur-bel-kala in 1056 BC, Assyria went into a comparative decline for the next 100 or so years.

The empire shrank significantly, and by 1020 BC, Assyria appears to have controlled only areas close to Assyria itself, essential to keeping trade routes open in eastern Aramea, South-Eastern Asia Minor, central Mesopotamia, and northwestern Iran.

Assyria once more began to expand with the rise of Adad-nirari II in 911 BC. He cleared Aramean and other tribal peoples from Assyria's borders and began to expand in all directions into Anatolia, Ancient Iran, Levant, and Babylonia.

Ashurnasirpal II (883–859 BC) continued this expansion apace, subjugating much of the Levant to the west, the newly arrived Persians and Medes to the east, annexed central Mesopotamia from Babylon to the south and expanded deep into Asia Minor to the north. He moved the capital from Ashur to Kalhu (Calah/Nimrud) and undertook impressive building works throughout Assyria.

Shalmaneser III (859–824 BC) projected Assyrian power even further, conquering the foothills of the Caucasus, Israel, and Aram-Damascus, and subjugating Persia and the Arabs who dwelt to the south of Mesopotamia, as well as driving the Egyptians from Canaan. It was during the reign of Shalmaneser III that the Arabs and Chaldeans first enter the pages of recorded history.

Little further expansion took place under Shamshi-Adad V and his successor, the regent queen Semiramis, however when Adad-nirari III (811–783 BC) came of age, he took the reins of power from mother and set about a relentless campaign of conquest; subjugated the Arameans, Phoenicians, Philistines, Israelites, Neo-Hittites and Edomites, Persians, Medes, and Manneans, penetrating as far as the Caspian Sea. He invaded and subjugated Babylonia, and then the migrant Chaldean and Sutean tribes settled in southeastern Mesopotamia whom he conquered and reduced to vassalage.

After the reign of Adad-nirari III, Assyria entered a period of instability and decline, losing its hold over most of its vassal and tributary territories by the middle of the 8th century BC, until the reign of Tiglath-Pileser III (745–727 BC). He created the world's first professional army, introduced Imperial Aramaic as the lingua franca of Assyria and its vast empire, and reorganized the empire drastically. Tiglath-Pileser III conquered as far as the East Mediterranean, bringing the Greeks of Cyprus, Phoenicia, Judah, Philistia, Samaria, and the whole of Aramea under Assyrian control. Not satisfied with merely holding Babylonia in vassalage, Tiglath-Pileser deposed its king and had himself crowned king of Babylon. The imperial, economic, political, military, and administrative reforms of Tiglath-Pileser III were to prove a blueprint for future empires, such as those of the Persians, Greeks, Romans, Carthaginians, Byzantines, Arabs, and Turks.

Shalmaneser V reigned only briefly, but once more drove the Egyptians from southern Canaan, where they were fomenting revolt against Assyria.

Sargon II quickly took Samaria, effectively ending the northern Kingdom of Israel and carrying 27,000 people away into captivity into the Israelite diaspora. He was forced to fight a war to drive out the Scythians and Cimmerians who had attempted to invade Assyria's vassal states of Persia and Media.

The Neo-Hittite states of northern Syria were conquered, as well as Cilicia. Lydia and Commagene. King Midas of Phrygia, fearful of Assyrian power, offered his hand in friendship. Elam was defeated and Babylonia and Chaldea reconquered.

Sargon II made a new capital city named Dur Sharrukin.

Sargon II was succeeded by his son Sennacherib who moved the capital to Nineveh and made the deported peoples work on improving Nineveh's system of irrigation canals. Nineveh was transformed into the largest city in the world at the time.

Esarhaddon had Babylon rebuilt, he imposed a vassal treaty upon his Persian, Median, and Parthian subjects, and he once more defeated the Scythes and Cimmerians.

Tiring Egyptian interference in the Assyrian Empire, Esarhaddon decided to conquer Egypt. In 671 BC he crossed the Sinai Desert, invaded, and took Egypt with surprising ease and speed. He drove its foreign Nubian/Kushite and Ethiopian rulers out, destroying the Kushite Empire in the process. Esarhaddon declared himself "king of Egypt, Libya, and Kush". Esarhaddon stationed a small army in northern Egypt and describes how; "All Ethiopians (read Nubians/Kushites) I deported from Egypt, leaving not one left to do homage to me". He installed native Egyptian princes throughout the land to rule on his behalf.

Under Ashurbanipal (669–627 BC), an unusually well-educated king for his time who could speak, read and write in Sumerian, Akkadian, and Aramaic, Assyrian domination spanned from the Caucasus Mountains (modern Armenia, Georgia, and Azerbaijan) in the north to Nubia, Egypt, Libya and Arabia in the south, and from the East Mediterranean, Cyprus and Antioch in the west to Persia, Cissia and the Caspian Sea in the east. Ultimately, Assyria conquered Babylonia, Chaldea, Elam, Media, Persia, Urartu (Armenia), Phoenicia, Aramea/Syria, Phrygia, the Neo-Hittite States, the Hurrian lands, Arabia, Gutium, Israel, Judah, Samarra, Moab, Edom, Corduene, Cilicia, Mannea, and Cyprus, and defeated and/or exacted tribute from Scythia, Cimmeria, Lydia, Nubia, Ethiopia, and others. At its height, the Empire encompassed the whole of the modern nations of Iraq, Syria, Egypt, Lebanon, Israel, Jordan, Kuwait, Bahrain, and Cyprus, together with large swathes of Iran, Saudi Arabia, Turkey, Sudan, Libya, Armenia, Georgia, and Azerbaijan.

The Assyrian Empire was severely crippled following the death of Ashurbanipal in 627 BC, the nation and its empire descending into a prolonged and brutal series of civil wars involving three rival kings, Ashur-etil-ilani, Sin-shumu-lishir and Sin-shar-ishkun. Egypt's 26th Dynasty, which had been installed by the Assyrians as vassals, quietly detached itself from Assyria, although it was careful to retain friendly relations.

The Scythians and Cimmerians took advantage of the bitter fighting among the Assyrians to raid Assyrian colonies, with hordes of horse-borne marauders ravaging parts of Asia Minor and the Caucasus, where the vassal kings of Urartu and Lydia begged their Assyrian overlord for help in vain. They also raided the Levant, Israel, and Judah (where Ashkelon was sacked by the Scythians) and all the way into Egypt whose coasts were ravaged and looted with impunity. The Iranic peoples under the Medes, aided by the previous Assyrian destruction of the hitherto dominant Elamites of Ancient Iran, also took advantage of the upheavals in Assyria to coalesce into a powerful Median-dominated force which destroyed the pre-Iranic kingdom of Mannea and absorbed the remnants of the pre-Iranic Elamites of southern Iran, and the equally pre-Iranic Gutians, Manneans and Kassites of the Zagros Mountains and the Caspian Sea.

Despite the sorely depleted state of Assyria, bitter fighting ensued; throughout 614 BC the Medes continued to gradually make hard-fought inroads into Assyria itself, scoring a decisive and devastating victory over the Assyrian forces at the battle of Assur.

In 613 BC, however, the Assyrians scored a number of counterattacking victories over the Medes-Persians, Babylonians-Chaldeans, and Scythians-Cimmerians.

This led to the unification of the forces ranged against Assyria who launched a massive combined attack, finally besieging and entering Nineveh in late 612 BC, with Sin-shar-ishkun being slain in the bitter street by street fighting.

During the aftermath, Egypt, along with remnants of the Assyrian army, suffered a defeat at the battle of Carchemish, in 605 BC, after which Assyria seems to have ceased to be an independent entity.

Despite the loss of almost all of its major cities, and in the face of overwhelming odds, Assyrian resistance continued under Ashur-uballit II (612–609 BC), who fought his way out of Nineveh and coalesced Assyrian forces around Harran which finally fell in 609 BC. The same year, Ashur-uballit II besieged Harran with the help of the Egyptian army, but this failed too, and this last defeat ended the Assyrian Empire.