Before the American Revolution, Hancock was one of the wealthiest men in the Thirteen Colonies, having inherited a profitable mercantile business from his uncle. He began his political career in Boston as a protégé of Samuel Adams, an influential local politician, though the two men later became estranged. Hancock used his wealth to support the colonial cause as tensions increased between colonists and Great Britain in the 1760s. He became very popular in Massachusetts, especially after British officials seized his sloopLiberty in 1768 and charged him with smuggling.

Hancock emerged as a leading political figure in Boston just as tensions with Great Britain were increasing. In March 1765, he was elected as one of Boston's five selectmen, an office previously held by his uncle for many years. After Bostonians learned of the impending repeal of the Stamp Act, Hancock was elected to the Massachusetts House of Representatives in May 1766.

On May 24, 1775, he was unanimously elected President of the Continental Congress, succeeding Peyton Randolph after Henry Middleton declined the nomination. He was experienced, having often presided over legislative bodies and town meetings in Massachusetts. His wealth and social standing inspired the confidence of moderate delegates, while his association with Boston radicals made him acceptable to other radicals. His position was somewhat ambiguous because the role of the president was not fully defined, and it was not clear if Randolph had resigned or was on a leave of absence. Like other presidents of Congress, Hancock's authority was mostly limited to that of a presiding officer.