In the U.S. state of West Virginia, U.S. Route 40 (US 40) runs for 16 miles (26 km) through the Northern Panhandle region. The highway enters the state on the Military Order of the Purple Heart bridge concurrent with US 250, crossing Wheeling Island, before joining Interstate 70 (I-70) over the Fort Henry Bridge before leaving the interstate. The highway travels north around Wheeling Hill, before traveling through the northeastern suburbs of Wheeling, Triadelphia and Valley Grove before entering Pennsylvania. A majority of the route still follows the old National Road which predates the U.S. Highway System.

U.S. Route 250 (US 250) is a United States Numbered Highway that runs from Sandusky, Ohio, to Richmond, Virginia. Within the state of West Virginia, the route runs from the Ohio border in Wheeling to the Virginia border near Thornwood.