The Kanawha or Buffalo Trail followed the Kanawha River from the Ohio River to Cedar Grove, then overland to Ansted. From there it followed the Meadow River and the Midland Trail (now U.S. 60) to Virginia. An alternate of this trail ran through Teays Valley from the Ohio River to the Kanawha River, near St. Albans. Another variation crossed the New River above the mouth of the Bluestone, passed through present Beckley, and followed Paint Creek north to the Kanawha River. This trail was used by the party of Shawnees who took Mary Ingles captive in 1755, during the raid on Drapers Meadows.

The Kanawha Trail also followed a portion of the route called the Ohio Branch of the Great Indian Warpath by William E. Myer in Indian Trails of the Southeast (1928). The Ohio Branch extended from Creek territory in Georgia and Alabama, up through eastern Tennessee and southwestern Virginia to the New and Kanawha rivers. At the mouth of the Kanawha several trails met. The main trail continued in a northwesterly direction through Ohio to Lake Erie.

There were numerous Indian villages along the Kanawha Trail until the middle 1600s. Exotic artifacts such as engraved marine shell gorgets from the eastern Tennessee region, as well as European copper and brass ornaments, and glass trade beads have been found at Pratt and Marmet, Kanawha County, and Buffalo, Putnam County, indicating movement along this route.