Knox was born in Boston on July 25, 1750. He attended the Boston Latin School but left to work in a bookstore. At the start of the Revolution, he quickly became a close advisor to General George Washington. Washington sent him to retrieve the British artillery captured at Fort Ticonderoga. Later, he marched with Washington in the retreat up Manhattan Island, at Trenton, Princeton, Brandywine, Germantown, Monmouth, Yorktown, Valley Forge, and Morristown. Knox briefly succeeded Washington as Commander-in-Chief, following the latter's retirement in 1783. He initiated the formation of the Society of the Cincinnati, a fraternity of American and French officers of the Revolution.
Knox was the first Secretary of War, entering the office in 1785 and remaining there for a decade. He supported the proposal for a federal Constitutional Convention, persuading the reluctant Washington to attend it. Later, he initiated the construction of the first ships built for the U.S. Navy. Knox retired from public office in 1796 and died at his estate near Thomaston, Maine, on October 25, 1806.