John Hancock inherited his uncle Thomas Hancock's mercantile business and became one of Boston's wealthiest merchants. Commercial connections, public generosity and election to local office helped establish his standing. He became a selectman in 1765 and entered the Massachusetts legislature the following year. Opposition to British taxation drew him toward Samuel Adams and other Patriot leaders, although the relationship involved rivalry as well as cooperation. The seizure of his vessel Liberty in 1768 and related smuggling allegations strengthened his popularity among opponents of customs enforcement; the charges were not successfully pursued.

Hancock used resources and political connections to support resistance as imperial relations deteriorated. He presided over the Massachusetts Provincial Congress after royal government lost authority. In April 1775 he and Adams were staying at Lexington when warnings of British movement prompted their departure. He then travelled to Philadelphia and was elected president of the Continental Congress in May. The position made him a presiding and coordinating officer, not the equivalent of a later executive president. He helped conduct Congress's business during the formation of the Continental Army and the move toward independence.

He held the presidency when Congress adopted the Declaration of Independence in 1776. His prominent signature and its appearance on early printed versions made his name inseparable from the document. Stories that he wrote especially large to taunt the king are later anecdotes rather than reliable evidence of his intentions. Congress's authority depended on state cooperation, and administration, supplies and military appointments produced recurring difficulties. Hancock left the presidency in 1777 and returned to Massachusetts. His participation in the unsuccessful Rhode Island expedition of 1778 also shows that prominence did not guarantee military effectiveness.

Elected governor under Massachusetts's new constitution in 1780, he held office until 1785 and again from 1787 until his death in 1793. His popular standing and relative willingness to ease fiscal pressure distinguished him from political opponents. At the state's ratifying convention in 1788 he helped secure acceptance of the federal Constitution through support for proposed amendments protecting liberties and clarifying powers. His wealth and popularity helped carry resistance into independent government.