The city of Tacoma and surrounding areas were inhabited for thousands of years by Native Americans, predominantly the Puyallup people, who lived in settlements on the delta. In 1852, a Swede named Nicolas Delin constructed a sawmill powered by water on a creek near the head of Commencement Bay, but the small settlement that grew up around it was abandoned during the Indian War of 1855–56.

In the 19th century the Clark Fork Valley was inhabited by the Flathead tribe of Native Americans. It was explored by Meriwether Lewis of the Lewis and Clark Expedition during the 1806 return trip from the Pacific. The river is named for William Clark. A middle segment of the river in Montana was formerly known as the Missoula River. The river was also referred to as the Deer Lodge River by Granville Stuart. David Thompson used the name Saleesh River for the entire Flathead-Clark Fork-Pend Oreille river system.