Already having been master of a ship at age 19, Hull was commissioned a lieutenant aboard the Constitution in 1798. He distinguished himself in the undeclared naval war with France at that time and in the Tripolitan War (1801–05); he was promoted to captain in 1806 and became commander of the Constitution four years later.

Encountering a British squadron in July 1812 off Egg Harbor, New Jersey, Hull escaped through consummate seamanship after three days and nights in one of the most remarkable chases in naval history. Sailing eastward of Boston, the Constitution met the Guerrière on August 19. After considerable maneuvering, under fire from the British ship, the American man-of-war delivered its first broadside, within pistol shot range. In fewer than 30 minutes of close and violent action, the Guerrière was demasted and rendered a total wreck. The helpless hulk was burned, and Hull returned to the mainland a hero. He was recognized as one of the navy's ablest commanders, and his ship became known as “Old Ironsides.”

Relieved of his command at his own request, Hull commanded harbour defenses at New York City and at three navy yards. He was one of the first three members of the Board of Naval Commissioners and commanded the U.S. squadron in the Pacific (1824–27) and the Mediterranean (1839–41).