In 1770 he was made surveyor of the district of Cumberland, and he subsequently became a justice of the court, of quarter sessions and of common pleas, a member of the proprietary council, a justice, recorder, and clerk of the orphans' court, and prothonotary of Bedford and Westmoreland counties. In July, 1775, he was made colonel of militia, and in the autumn he accompanied as secretary the commissioners that were appointed to treat with the western tribes at Fort Pitt. On 3 January, 1776, he became colonel of the 2d Pennsylvania regiment, and, being ordered to Canada, he joined General John Sullivan after the disastrous affair at Three Rivers, and aided that officer by his counsel, saving the army from capture, fie was appointed brigadier-general on 9 August, 1776, having resigned his civil offices in the previous January. Joining General Washington in November, 1776, he was appointed to organize the New Jersey militia, and participated in the battles of Trenton and Princeton. On the latter occasion he rendered valuable service by protecting the fords of the Assanpink. 

He was appointed major-general on 19 February, 1777, and, after serving as adjutant-general of the army, succeeded Gem Horatio Gates in command at Ticonderoga. The works there and at Mount Independence on the opposite shore of Lake Champlain were garrisoned by less than 2,000 men, poorly armed, and nearly destitute of stores. The approach of a force of more than 7,000 men under General John Burgoyne warned General St. Clair to prepare for an attack. His force was too small to cover all exposed points, and, as he had not discovered Burgoyne's designs, he neglected to fortify Sugar Loaf mountain over which the British approached. St. Clair and his officers held a council of war, and decided to evacuate the fort. The blaze of a house that had been set on fire contrary to orders discovered their movements, and immediately the British started in pursuit. St. Clair fled through the woods, leaving a part of his force at Hubbardton, which was attacked and defeated by General Fraser on 7 July, 1777, after a well-contested battle. On 12 July, St. Clair reached Fort Edward with the remnant of his men. "The evacuation," wrote Washington, when the news reached him, " is an event of chagrin and surprise not apprehended, nor within the compass of my reasoning. This stroke is severe indeed, and has distressed us much."

He was a member of the Pennsylvania council of censors in 1783, a delegate to the Continental congress from 2 November, 1785, till 28 November, 1787, and its president in 1787, and a member of the American philosophical society. On the formation of the Northwestern territory in 1789 General St. Clair was appointed its governor, holding this office until 1802. The last words of Washington on his departure were : "Beware of a surprise."

He made a treaty with the Indians at Fort Harmar in 1789, and in 1790 he fixed the seat of justice of the territory at Cincinnati, Ohio, which he named in honor of the Society of the Cincinnati, of which he was president for Pennsylvania in 1783-'9. He was appointed commander-in-chief of the army that was operating against the Indians on 4 March, 1791, and moved toward the savages on Miami and Wabash rivers, suffering so severely from gout that he was carried on a litter. He was surprised near the Miami villages on 4 November, and his force was defeated by a horde of Indians led by Blue Jacket, Little Turtle, and Simon Girty, the renegade.

Washington refused a court of inquiry, and St. Clair resigned his general's commission on 5 March, 1792, but congress appointed a committee of investigation, which exonerated him. On 22 November, 1802, he was removed from his governorship by Thomas Jefferson. Retiring to a small log-house on the summit of Chestnut ridge, he spent the rest of his life in poverty, vainly endeavoring to effect a settlement of his claims against the government. The legislature of Pennsylvania granted him an annuity of $8400 in 1813, and shortly before his death he received from congress $2,000 in discharge of his claims, and a pension of $60 a month.

He published "A Narrative of the Manner in which the Campaign against the Indians in the Year 1791 was conducted under the Command of Major-General St. Clair, with his Observations on the Statements of the Secretary of War" (Philadelphia, 1812). See "The Life and Public Services of Arthur St. Clair," with his correspondence and other papers, arranged by William H. Smith (Cincinnati, 1882).