Immigrating to North America in 1765, Wilson taught Greek and rhetoric in the College of Philadelphia and then studied law under John Dickinson, statesman and delegate to the First Continental Congress. Wilson's fame spread with publication in 1774 of his treatise Considerations on the Nature and Extent of the Legislative Authority of the British Parliament. In this work he set out a scheme of empire in which the British colonies would have the equivalent of dominion status. In 1774 he became a member of the Committee of Correspondence in Cumberland County, Pa., and he served as a delegate to the Second Continental Congress. In 1779 he was appointed advocate general for France and represented that country in cases rising out of its alliance with the American colonies. He became a champion of the Bank of North America and an associate of merchant-banker Robert Morris in his struggle for currency reform after 1781. As a member of the federal Congress (1783; 1785–86), he pressed for an amendment to the Articles of Confederation to permit Congress to levy a general tax.

During the Constitutional Convention in 1787, Wilson helped to draft the U.S. Constitution; he then led the fight for ratification in Pennsylvania. In 1790 he engineered the drafting of Pennsylvania's new constitution and delivered a series of lectures that are landmarks in the evolution of American jurisprudence. He was appointed an associate justice of the U.S. Supreme Court (1789–98), where his most notable decision was that on Chisholm v. Georgia. In the winter of 1796–97 financial ruin brought on by unwise land speculation shattered his health and ended his career.