In 1768, the year after his admission to the Philadelphia bar, Wilson set up practice at Reading, Pa. Two years later, he moved westward to the Scotch-Irish settlement of Carlisle, and the following year he took a bride, Rachel Bird. He specialized in land law and built up a broad clientele. On borrowed capital, he also began to speculate in land. In some way he managed, too, to lecture on English literature at the College of Philadelphia, which had awarded him an honorary master of arts degree in 1766.

Wilson became involved in Revolutionary politics. In 1774 he took over chairmanship of the Carlisle committee of correspondence, attended the first provincial assembly, and completed preparation of Considerations on the Nature and Extent of the Legislative Authority of the British Parliament. This tract circulated widely in England and America and established him as a Whig leader.

The next year, Wilson was elected to both the provincial assembly and the Continental Congress, where he sat mainly on military and Indian affairs committees. In 1776, reflecting the wishes of his constituents, he joined the moderates in Congress voting for a 3-week delay in considering Richard Henry Lee's resolution of June 7 for independence. On the July 1 and 2 ballots on the issue, however, he voted in the affirmative and signed the Declaration of Independence on August 2.

Wilson's strenuous opposition to the republican Pennsylvania constitution of 1776, besides indicating a switch to conservatism on his part, led to his removal from Congress the following year. To avoid the clamor among his frontier constituents, he repaired to Annapolis during the winter of 1777-78 and then took up residence in Philadelphia.

Wilson affirmed his newly assumed political stance by closely identifying with the aristocratic and conservative republican groups, multiplying his business interests, and accelerating his land speculation. He also took a position as Advocate General for France in America (1779-83), dealing with commercial and maritime matters, and legally defended Loyalists and their sympathizers.

In the fall of 1779, during a period of inflation and food shortages, a mob which included many militiamen and was led by radical constitutionalists, set out to attack the republican leadership. Wilson was a prime target. He and some 35 of his colleagues barricaded themselves in his home at Third and Walnut Streets, thereafter known as "Fort Wilson." During a brief skirmish, several people on both sides were killed or wounded. The shock cooled sentiments and pardons were issued all around, though major political battles over the commonwealth constitution still lay ahead.

During 1781 Congress appointed Wilson as one of the directors of the Bank of North America, newly founded by his close associate and legal client Robert Morris. In 1782, by which time the conservatives had regained some of their power, the former was reelected to Congress, and he also served in the period 1785-87.

Wilson reached the apex of his career in the Constitutional Convention (1787), where his influence was probably second only to that of Madison. Rarely missing a session, he sat on the Committee of Detail and in many other ways applied his excellent knowledge of political theory to convention problems. Only Gouverneur Morris delivered more speeches.

That same year, overcoming powerful opposition, Wilson led the drive for ratification in Pennsylvania, the second state to endorse the instrument. The new commonwealth constitution, drafted in 1789-90 along the lines of the U.S. Constitution, was primarily Wilson's work and represented the climax of his 14-year fight against the constitution of 1776.

For his services in the formation of the federal government, though Wilson expected to be appointed Chief Justice of the Supreme Court, in 1789 President Washington named him as an associate justice. He was chosen that same year as the first law professor at the College of Philadelphia. Two years later he began an official digest of the laws of Pennsylvania, a project he never completed, though he carried on for a while after funds ran out.

Wilson, who wrote only a few opinions, did not achieve the success on the Supreme Court that his capabilities and experience promised. Indeed, during those years he was the object of much criticism and barely escaped impeachment. For one thing, he tried to influence the enactment of legislation in Pennsylvania favorable to land speculators. Between 1792 and 1795 he also made huge but unwise land investments in western New York and Pennsylvania, as well as in Georgia. This did not stop him from conceiving a grandiose but ill-fated scheme, involving vast sums of European capital, for the recruitment of European colonists and their settlement in the West. Meantime, in 1793, as a widower with six children, he remarried to Hannah Gray; their one son died in infancy.

Four years later, to avoid arrest for debt, the distraught Wilson moved from Philadelphia to Burlington, NJ. The next year, apparently while on federal circuit court business, he arrived at Edenton, NC, in a state of acute mental stress and was taken into the home of James Iredell, a fellow Supreme Court justice. He died there within a few months. Although first buried at Hayes Plantation near Edenton, his remains were later reinterred in the yard of Christ Church at Philadelphia.