By the mid-1770s, St. Clair considered himself more of an American than a British subject. In January 1776, he accepted a commission in the Continental Army as a colonel of the 3rd Pennsylvania Regiment. He first saw service in the later days of the Quebec invasion, where he saw action in the Battle of Trois-Rivières. He was appointed a brigadier general in August 1776, and was sent by Gen. George Washington to help organize the New Jerseymilitia. He took part in George Washington's crossing of the Delaware River on the night of December 25–26, 1776, before the Battle of Trenton on the morning of December 26. Many biographers credit St. Clair with the strategy that led to Washington's capture of Princeton, New Jersey, on January 3, 1777. St. Clair was promoted to major general in February 1777.

After the war, he served as President of the Continental Congress, which during his term passed the Northwest Ordinance. He was then made governor of the Northwest Territory in 1788, and then the portion that would become Ohio in 1800. In 1791, St. Clair commanded the American forces in what was the United States' worst-ever defeat by the Native Americans, which became known as St. Clair's defeat. Politically out-of-step with the Jefferson administration, he was replaced as governor in 1802.