The source of the mainstem Big Hole River is Skinner Lake in the Beaverhead National Forest in the Beaverhead Mountains of the Bitterroot Range at the Continental Divide along the Montana-Idaho border in western Beaverhead County. However, Skinner Lake is in turn fed by Darkhorse Creek, which flows from Darkhorse and Cowbone Lakes, the former at . The Big Hole River flows northwest and north, past Wisdom and between the Anaconda Range to the northwest and the Pioneer Mountains to the east. It flows around the north end of the Pioneers where it forms the border between Beaverhead County and Deer Lodge County and then Silver Bow County, then southeast past the town of Wise River, Montana, where it is joined by the Wise River. Near Glen, Montana it turns northeast and joins the Beaverhead River near Twin Bridges to form the Jefferson.