Zayed was born in Abu Dhabi in 1918, he was the youngest of four sons of Sheikh Sultan bin Khalifa Al Nahyan. His father was the ruler of Abu Dhabi from 1922 until his assassination in 1926.

He have moved from Abu Dhabi to Al Ain in 1927, after the assassination of his father. As Zayed was growing up in Al-Ain, there were no modern schools anywhere along the coast. He only received a basic instruction in the principles of Islam, and lived in the desert with Bedouin tribesmen, familiarizing himself with the life of the people, their traditional skills and their ability to survive under the harsh climatic conditions.

Zayed was appointed the governor of the Eastern Region of Abu Dhabi in 1946, and was based in the Muwaiji fort in Al Ain. At this time, the area was poor and prone to outbreaks of disease. When parties from Petroleum Development (Trucial Coast) began exploring for oil in the area, Zayed assisted them.

The discovery of oil in 1958, and the start of oil exports in 1962, led to frustration among members of the ruling family about the lack of progress under Sheikh Shakhbut’s rule. On 6 August 1966, Shakhbut was deposed in a bloodless palace coup. The move to replace Shakhbut with Zayed had the unanimous backing of the Al Nahyan family. The news was conveyed to Shakhbut by British Acting Resident Glen Balfour-Paul who added the support of the British to the consensus of the family. Shakhbut finally accepted the decision and, with the Trucial Oman Scouts providing safe transport, left for Bahrain. He subsequently lived in Korramshahr, Iran before returning to live in Buraimi.

Between 8–11 January 1968, the UK's Foreign Office Minister Goronwy Roberts visited the Trucial States and announced to its shocked rulers that the United Kingdom would abrogate its treaties with them and intended to withdraw from the area.

In a seminal meeting on 18 February 1968 at a desert highland on the border between Dubai and Abu Dhabi, Sheikh Zayed and Sheikh Rashid bin Saeed Al Maktoum of Dubai shook hands on the principle of founding a Federation and attempting to invite other trucial rulers to join in order that a viable nation be formed in the wake of the British withdrawal.

At the time the British withdrew from the Persian Gulf in 1971, Zayed oversaw the establishment of the Abu Dhabi Fund for Arab Economic Development; some of its oil riches were channeled to some forty less fortunate Islamic nations in Asia and Africa during the decades that followed.

After the United Arab Emirates was formed, Zayed became the Supreme Commander of The Armed Forces.

In 1971, after occasionally difficult negotiations with the other six rulers of the Trucial States, the United Arab Emirates was formed. Zayed was appointed to the presidency of the UAE in 1971 and was reappointed on four more occasions: 1976, 1981, 1986, and 1991.

In 1974, Zayed settled the outstanding border dispute with Saudi Arabia by the Treaty of Jeddah by which Saudi Arabia received the output of the Shaybah oilfield and access to the lower Persian Gulf in return for recognizing the UAE.

On 2 November 2004, Zayed died at the age of 86. He was buried in the courtyard of the new Sheikh Zayed Mosque in Abu Dhabi.