The pass is the highest point of the historic Lolo Trail, between the Bitterroot Valley in Montana and the Weippe Prairie in Idaho.

The Lolo Trail is a National Historic Landmark, designated for its importance to the Lewis and Clark Expedition, and its role in the 1877 Nez Perce War.

Its first known mention is in the 1810 journal of David Thompson, who described three fur trappers, probably of French descent, named Michael, Lolo, and Gregoire.

The primary city in Idaho served by U.S. 12 is Lewiston, 170 miles (270 km) west of the pass at the border with Washington, where the Clearwater meets the Snake.

On March 1, 2014, the Idaho Department of Fish and Game announced that 23 wolves had been killed in the Lolo Pass area, in order to boost elk populations.