His erudition had brought him into contact with some of the leading intellectuals of the Patriot cause and, in turn, with the ferment of political ideas that eventually found expression in the Constitution.
His experiences in that preeminent event of his generation transformed the genial scholar into an adroit politician and a determined leader in the campaign for effective national government.
He moved to Connecticut and obtained a preacher's license but his disillusionment with factional disputes within the Presbyterian Church and a resurgence of ill health led him to abandon a career in the ministry.
At the same time, he pursued a number of independent scientific and educational projects, and his work in these areas eventually led to membership in the American Philosophical Society as well as acclaim in Europe's intellectual circles.
In response to questions by Council members, who were in the process of formulating punitive measures against Massachusetts, he bluntly warned that repression would provoke rebellion.
He then went on to express the argument that was becoming the core of the Patriot position: Americans were entitled to the full rights of Englishmen, including representation in the decisions of the English government.
Williamson continued on to the Netherlands where, taking advantage of the cover afforded by his attendance at meetings on scientific and educational subjects, he organized the publication of pamphlets and other papers that supported the Patriot cause.
The department had no opening at that time, so Williamson decided to form a partnership with a younger brother to import medicines and other scarce items from the West Indies through the British blockade.
Facing the threat of a British invasion of the region from the sea and bases in Florida, the state legislature voted to raise a force of 4,000 men to assist South Carolina.
Gates attempted to attack the British advance base near Camden, South Carolina, but his tired militia units, which were still forming when the battle began, were routed, and the Americans suffered another defeat.
Major General Nathanael Greene, Gates' replacement, had begun his brilliant campaign to recover the south through the joint efforts of continentals and militia.
Williamson's bold innovations in preventive medicine, especially his strenuous efforts to indoctrinate raw troops in the importance of sanitation and diet, kept the command virtually free of disease during the six months that it inhabited the swamp-—a rare feat in 18th-century warfare.
In 1786 North Carolina chose Williamson to attend the Annapolis Convention, a meeting called to settle economic questions affecting the middle Atlantic states.
Although he arrived too late to play a role in the Maryland proceedings, he was prepared to discuss interstate issues the following year when his state-appointed him as a representative at the Constitutional Convention in Philadelphia.
Williamson, a faithful attendee at Convention sessions, lodged with Alexander Hamilton and James Madison, two of the country's best-known nationalist leaders.
Using simple examples, Williamson explained to both groups the dual dangers of inflationary finances and of taxes that would stunt the growth of domestic manufacture.
The ratification process, he explained, would decide whether the United States would remain a "system of patchwork and a series of expedients" or become "the most flourishing, independent, and happy nation on the face of the earth."
Following adjournment in Philadelphia, Williamson returned to New York to participate in the closing sessions of the Continental Congress and to serve as one of the agents settling North Carolina's accounts with that body.
Thomas Jefferson described Williamson's role at the Philadelphia Convention in the following terms: "he was a useful member, of an acute mind, attentive to business, and of a high degree of erudition."