Forced by family circumstances to leave school at age nine, Knox worked in a Boston bookstore and by age 21 had acquired his own store. He became active in the colonial militia and in 1775 joined the Continental Army at Cambridge, Massachusetts. He was commissioned a colonel and placed in charge of the artillery. During the winter of 1775–76 General George Washington (Washington, George) sent him to Fort Ticonderoga, in New York, to bring back captured British artillery there. In a remarkable feat, Knox brought back artillery totaling 120,000 pounds (55,000 kg), using oxen, horses, and men to transport the guns over snow and ice 300 miles (480 km) to Boston. The weapons were used to drive the British from that besieged city and formed the basis for the Revolutionary artillery.

In the Philadelphia campaign (1778), Knox, then a brigadier general, distinguished himself in commanding the artillery at Monmouth (Monmouth, Battle of), New Jersey (June), and later at the decisive Siege of Yorktown (Yorktown, Siege of) (1781). He was made a major general and at the end of the war succeeded Washington as commander of the army (December 1783). Knox resigned his command early in 1784 and returned to Boston. He became secretary of war (1785) in the government under the Articles of Confederation and was carried over into President Washington's first cabinet (1789). He retired to a large estate at Thomaston, Maine, in 1795.