U.S. Route 60 (US 60) runs northwest to southeast across the central and southern portions of West Virginia. It runs from the Kentucky state line at Catlettsburg, Kentucky, and Kenova. The road passes through Huntington, Charleston, and White Sulphur Springs. The route exits the state into Virginia, running concurrently with Interstate 64 (I-64) east of White Sulphur Springs. Most of US 60's route through West Virginia is part of and even signed in several areas as the Midland Trail, a National Scenic Byway.

U.S. Route 219 (US 219) is a part of the U.S. Highway System that travels from Rich Creek, Virginia, to West Seneca, New York. In the U.S. state of West Virginia, the U.S. Highway travels from the Virginia state line near Peterstown to the Maryland state line near Silver Lake.