Via the Gauley, Kanawha and Ohio Rivers, it is part of the watershed of the Mississippi River, draining an area of 132 square miles (342 km2) in a sparsely populated region of the southern Allegheny Mountains and the unglaciated portion of the Allegheny Plateau.

[10] The Williams River rises in southern Pocahontas County, approximately 5 miles (8 km) west of Marlinton, and flows initially northwardly, then westwardly into southern Webster County, where it joins the Gauley River approximately 2 miles (3 km) southeast of Cowen.

[7] It flows for much of its length in the Monongahela National Forest, including the Cranberry Wilderness, in an area that was heavily logged in the early 20th century and has since been reforested.

Coal mining activity took place along the river's lower course into the 1970s.

[6] The Williams River is regarded as one of the five best trout fishing streams in West Virginia,[6] due to its cold water temperature, low turbidity, and frequent stockings of trout (amounting to 27,000 pounds annually) by the West Virginia Division of Natural Resources.