Clinton was the son of Charles Clinton, a farmer and surveyor, and Elizabeth Denniston. He served in the last French and Indian War (1756–63) and was a member of the New York Assembly (1768–75) and the Continental Congress. In the summer of 1776, before he could sign the Declaration of Independence, he was ordered by General George Washington (Washington, George) to New York City. In March 1777 he was appointed brigadier general.

Immensely popular with the people of New York, Clinton was elected governor in 1777, serving 21 years (1777–95; 1801–04) as a forceful leader and able administrator. Fearful of threats to his political power in New York, he argued against ratification of the United States Constitution (Constitution of the United States of America), maintaining that the power granted to the national government to regulate commerce would undermine New York's commercial advantages.

In national politics Clinton was a follower of Jefferson and was elected as his vice president in 1804. After an unsuccessful attempt to win nomination for president in 1808 he was reelected vice president under Madison. He died before the expiration of his second term, the first vice president to die in office.