Born into a wealthy merchant family, Gerry vocally opposed British colonial policy in the 1760s and was active in the early stages of organizing the resistance in the American Revolutionary War. Elected to the Second Continental Congress, Gerry signed both the Declaration of Independence and Articles of Confederation.

He was one of three men who attended the Constitutional Convention in 1787, but refused to sign the Constitution because originally it did not include a Bill of Rights. After its ratification, he was elected to the inaugural United States Congress, where he was actively involved in the drafting and passage of the Bill of Rights as an advocate of individual and state liberties.

Gerry was at first opposed to the idea of political parties and cultivated enduring friendships on both sides of the political divide between Federalists and Democratic-Republicans. He was a member of a diplomatic delegation to France that was treated poorly in the XYZ Affair, in which Federalists held him responsible for a breakdown in negotiations. Gerry thereafter became a Democratic-Republican, running unsuccessfully for Governor of Massachusetts several times before winning the office in 1810. During his second term, the legislature approved new state senate districts that led to the coining of the word "gerrymander"; he lost the next election, although the state senate remained Democratic-Republican.