Born in Caroline County, Virginia, Clark moved with his family to Louisville, Kentucky in 1785. After his brother George joined the army, William Clark followed, and participated in several local militia campaigns. He was commissioned a lieutenant in the regular army in 1792, and was assigned to Anthony Wayne's regiment, where he served a four-year tour and participated in the Battle of Fallen Timbers. Also during this period, one of the men briefly under his command was Meriwether Lewis.
Clark left the army in 1796, spending time at his estate in Louisville and traveling from time to time. In 1803 he was asked by Lewis to share command of the newly-formed Corps of Discovery. Clark spent three years on the excursion, and although technically subordinate to Lewis in rank, tended to exercise equal authority. He concentrated chiefly on the drawing of maps and the identification of native flora and fauna, and after returning in 1806 spent a great deal of time consolidating the information collected.
Clark was appointed a brigadier general of the militia and made superintendent of Indian affairs in the Louisiana Territory in 1807. He set up his headquarters for this in St. Louis, Missouri. When the Missouri Territory was formed in 1813 Clark was appointed governor. During the War of 1812 he led several campaigns, and established the first post in what is now Wisconsin.
After the war Clark returned to the administration of Indian affairs, employing various diplomatic and military measures in response to several uprisings in the area. Additionally, he worked as a surveyor. He died in St. Louis.