The river flows northwest through a long valley at the base of the Cabinet Mountains and empties into Lake Pend Oreille in the Idaho Panhandle.

The Pend Oreille River in Idaho, Washington, and British Columbia, Canada which drains the lake to the Columbia in Washington, is sometimes included as part of the Clark Fork, giving it a total length of 479 miles (771 km), with a drainage area of 25,820 square miles (66,900 km2).

The highest point within the river's watershed is Mount Evans at 10,641 feet (3,243 m) in Deer Lodge County, Montana along the Continental Divide.

[12] The Clark Fork is a Class I river for recreational purposes in Montana from Warm Springs Creek to the Idaho border.

From Deer Lodge it flows generally northwest across western Montana, passing south of the Garnet Range toward Missoula.

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 5.5 miles (8.9 km) west of downtown Missoula.

After passing the Cabinet Gorge Dam, the river enters the northeastern end of Lake Pend Oreille, approximately 8 miles (13 km) west of the Idaho–Montana border, near the town of Clark Fork, Idaho.During the last ice age, from approximately 20,000 years ago, the Clark Fork Valley lay along the southern edge of the Cordilleran Ice Sheet covering western North America.

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.

[18] 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.