William Clark was born in Caroline County, Virginia, on August 1, 1770, the ninth of the ten children of John and Ann Rogers Clark. His parents were natives of King and Queen County, and were of English and possibly Scottish ancestry. The Clarks were of the lesser Virginia gentry, owners of modest estates and a few slaves, and members of the Anglican Church.

Clark did not have any formal education, but like many of his contemporaries he was tutored at home. In later years, he was somewhat self - conscious about his convoluted grammar and inconsistent spelling — he spelled "Sioux" 27 different ways in his journals of the Lewis and Clark Expedition — and sought to have his journals corrected before publication. But the spelling of American English was not standardized in Clark's youth, and his vocabulary suggests that he was well read.

Clark's five older brothers fought in Virginia units during the American Revolutionary War (1775 – 1783), but William was too young to go off to battle. His oldest brother, Jonathan Clark, served as a colonel during the war, rising to the rank of general in the Virginia militia years afterward. His second oldest brother, George Rogers Clark, rose to the rank of general, spending most of the war in Kentucky fighting against British allied American Indians. After the war, the two oldest Clark brothers made arrangements for their parents and family to relocate to Kentucky.

William, his parents, his three sisters, and the Clark family's slaves arrived in Kentucky in March 1785, having first traveled overland to Redstone Landing in present day Brownsville, Pennsylvania. They completed the journey down the Ohio River by flatboat. The Clark family settled at "Mulberry Hill", a plantation along Beargrass Creek near Louisville. This would be William Clark's primary home until 1803. In Kentucky, his older brother George Rogers Clark taught William wilderness survival skills.
Although the Revolutionary War was over, Kentuckians continued to fight the Northwest Indian War with American Indians north of the Ohio River. In 1789, nineteen year old William Clark began his military career by joining a volunteer militia force under Major John Hardin. Clark kept a detailed journal of the expedition, the beginning of a lifelong practice. The targets of Hardin's expedition were Wea Indians on the Wabash River who had been raiding settlements in Kentucky. The undisciplined Kentucky militia attacked a peaceful Shawnee hunting camp, where they killed a total of eight men, women, and children.

In 1790, Clark was commissioned by General Arthur St. Clair, governor of the Northwest Territory, as a captain in the Clarksville, Indiana militia. The nature of his services that year are unclear; one older source says that he was sent on a mission to the Creek and Cherokee Indians. He may have visited New Orleans at that time. His travels prevented him from participating in General Josiah Harmar's disastrous campaign into the Northwest Territory that year.

In 1791, Clark served as an ensign and acting lieutenant with expeditions under generals Charles Scott and James Wilkinson. Clark enlisted in the Legion of the United States and was commissioned as a Lieutenant on March 6, 1792 under Anthony Wayne. On September 4, 1792 he was assigned to the 4th Sub-Legion. He was involved in several skirmishes with Indians during the continuing Northwest Indian War. At the Battle of Fallen Timbers in 1794, Clark commanded a company of riflemen who drove back the enemy on the left flank, killing a number of Indians and Canadians. This decisive US victory brought the Northwest Indian War to an end. In 1795, Clark was dispatched on a mission to New Madrid, Missouri. Clark also served as an adjutant and quartermaster while in the militia.

William Clark resigned his commission on July 4, 1796 and retired due to poor health, although he was only 26 years old. He returned to Mulberry Hill, his family's plantation near Louisville. Prior to his resignation, Meriwether Lewis had been assigned to Clark's unit as an ensign under Clark's command, and they came to respect each other.

In 1803, Lewis recruited Clark, then age 33, to share command of the newly formed Corps of Discovery, whose mission it was to explore the territory of the Louisiana Purchase, establish trade and sovereignty, and find a water way from the 13 colonies to the pacific and claim the Oregon territory for the United States before European nations. Clark spent three years on the expedition to the Pacific Coast. A slave owner who dealt harshly with his slaves, he brought one of his slaves York with him, who performed manual labour in extreme weather and received no compensation. The indigenous nations treated York with respect, and some were interested in his appearance, which "played a key role in diplomatic relations". Although Clark was refused rank when Jefferson asked the Senate to appoint him, at Lewis' insistence, he exercised equal authority, and continued the mission. Clark concentrated chiefly on the drawing of maps, the management of the expedition's supplies, and the leading of men in hunting.

Clark was appointed by President Jefferson as the brigadier general of the militia in the Louisiana Territory in 1807, which made him the agent for Indian affairs. He set up his headquarters in St. Louis, Missouri. There Clark was a member of the Freemasons. The records of his initiation do not exist, but on September 18, 1809, Saint Louis Lodge No. 111 issued a traveling certificate for Clark.

During the War of 1812, he led several campaigns, among them in 1814 one along the Mississippi River, up to the Prairie du Chien area, where he established the short lived Fort Shelby, the first post in what is now Wisconsin. Soon the post was captured by the British.

When the Missouri Territory was formed in 1813, Clark was appointed as the governor by President Madison. He was re-appointed to the position by Madison in 1816, and in 1820 by President Monroe. When Missouri became a state in 1820, Clark was defeated in the election for governor by Alexander McNair. In 1822, he was appointed Superintendent of Indian Affairs by President Monroe, a new position created by Congress after the factory system was abolished. Clark remained in that capacity until his death, his title changed with the creation of the Office of Indian Affairs in 1824 and finally the Bureau of Indian Affairs in 1829, both within the War Department. From 1824 to 1825, he was additionally appointed surveyor general of Illinois, Missouri and the Territory of Arkansaw.

Though Clark tried to maintain peaceful relations with indigenous nations and negotiated peace treaties, he was involved in President Andrew Jackson's Indian removal policy. This included "his duty to oversee removal", and retaliation against Black Hawk and those allied with him in the Black Hawk War when hostilities arose between them and the Americans. Clark made "an extermination order", which he gave to Lewis Cass, a man who played a central role in Jackson's removal policy.

Clark married Julia Hancock on January 5, 1808, at Fincastle, Virginia, and they had five children: Meriwether Lewis Clark, Sr. (1809 – 1881) named after his friend and expedition partner; William Preston Clark (1811 – 1840); Mary Margaret Clark (1814 – 1821); George Rogers Hancock Clark (1816 – 1858), named after Clark's older brother; and John Julius Clark (1818 – 1831), named after his oldest brother Jonathan and Clark's wife.

After Julia's death in 1820, William Clark married her first cousin, Harriet Kennerly Radford. They had another three children together: Jefferson Kearny Clark (1824 – 1900), named after the president; Edmund Clark (1826 – 1827); and Harriet Clark, named after her mother (dates unknown; died as child). His second wife Harriet died in 1831.

Clark died in St. Louis on September 1, 1838. He was buried there in the Bellefontaine Cemetery, where a 35 foot (11 m) gray granite obelisk was erected to mark his grave. The cemetery has been designated a National Historic Landmark.

Although his family had established endowments to maintain his grave site, by the late 20th century the grave site had fallen into disrepair. His descendants raised $100,000 to rehabilitate the obelisk. They celebrated the re-dedication with a ceremony May 21, 2004, on the bicentennial of the start of the Lewis & Clark Expedition. The ceremony was attended by a large gathering of his descendants, reenactors in period dress, and leaders from the Osage Nation and the Lemhi band of the Shoshone people.

• In 2001, President Bill Clinton elevated Clark to a Captain in the US Army posthumously. Descendants of Clark were there to mark the occasion.

• The western American plant genus Clarkia (in the Evening primrose family Onagraceae), is named after him, as are the cutthroat trout (Oncorhynchus clarki), Clark's Grebe (Aechmophorus clarkii), and Clark's Nutcracker (Nucifraga columbiana), a large passerine bird, in the family Corvidae. All were species which Clark identified during the expedition.

• A star with his name is part of the St. Louis Walk of Fame.
• Counties were named in his honor in the following states: Arkansas, Idaho, Missouri, Lewis and Clark County, Montana, and Washington.
• The Clarks River in western Kentucky is named for him, as is the Clark Fork in Montana and Idaho, and the Clarks Fork Yellowstone River in Montana and Wyoming.
• The United States Navy Polaris nuclear submarine USS Lewis and Clark was named for him and Meriwether Lewis.
• The Clark Bridge is a cable - stayed bridge across the Mississippi River between West Alton, Missouri, and Alton, Illinois, was named after the great explorer.
• Lewis and Clark Community College is a comprehensive community college in the Metro East region of St. Louis, Mo. (on the Illinois side of the Mississippi River) near Alton, Illinois, was named after Meriwether Lewis and William Clark.
• Lewis and Clark Law School in Portland Oregon was named after Meriwether Lewis and William Clark.