It rises as Silver Bow Creek in southwestern Montana, less than 5 mi (8 km) from the continental divide near downtown Butte, from the confluence of Basin and Blacktail creeks. It flows northwest and north through a valley in the mountains, passing east of Anaconda, where it changes its name to the Clark Fork, then northwest to Deer Lodge. From Deer Lodge it flows generally northwest across western Montana, passing south of the Garnet Range toward Missoula. Five miles east of Missoula, the river receives the Blackfoot River.
Northwest of Missoula, the river continues through a long valley along the northeast flank of the Bitterroot Range, through the Lolo National Forest. It receives the Bitterroot River from the south-southwest approximately 5 1/2mi west of downtown Missoula, and receives the Flathead River from the north near Paradise. It receives the Thompson River from the west near Thompson Falls in southern Sanders County.
At Noxon, Montana, along the north end of the Bitterroots near the Idaho border, the river is impounded by the Noxon Rapids Dam to form a 20 mi (32 km) long reservoir. It crosses into western Bonner County in northern Idaho near the town of Cabinet, Idaho. Approximately 5 mi (8 km) west of the Idaho-Montana state line, the river enters the eastern end of Lake Pend Oreille, near the town of Clark Fork.
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.
In 1809 David Thompson of the North West Company explored the region and founded several fur trading posts, including Kullyspell House at the mouth of the Clark Fork, and Saleesh House on the river near the present-day site of Thompson Falls, Montana. Thompson used the name Saleesh River for the entire Flathead-Clark Fork-Pend Oreille river system. For most of the first half of the 19th century the Clark Fork river and surrounding region was controlled by the British-Canadian North West Company and Hudson's Bay Company.
Since the late 19th century many areas in the watershed of the river have been extensively mined for minerals, resulting in an ongoing stream pollution problem. Most pollution has come from the copper mines in Butte and the smelter in Anaconda. Many of the most polluted areas have been designated as Superfund sites. Nevertheless the river and its tributaries are among the most popular destinations for fly fishing in the United States.
Today, the Clark Fork watershed encompasses the largest Superfund site in America. As a mega-site, it includes three major sites: Butte, Anaconda, and Milltown Dam/Clark Fork River. Each of these major sites is split up into numerouse sub-sites known as Operable Units. Remediation and/or restoration of these sites is ongoing.