U.S. Route 50 in West Virginia runs from the border with Ohio to Virginia, passing briefly through Garrett County, Maryland, and following the Northwestern Turnpike. Prior to the U.S. Highway System it was West Virginia Route 1 and in the 1930s, the road was not finished in Maryland. Today the section of US 50 from Clarksburg to Parkersburg on the Ohio River is part of Corridor D of the Appalachian Development Highway System.

The Northwestern Turnpike is a historic road in West Virginia, important for being historically one of the major roads crossing the Appalachians, financed by the Virginia Board of Public Works in the 1830s. In modern times, west of Winchester, Virginia, U.S. Route 50 follows the path of the Northwestern Turnpike into West Virginia, whose major Corridor D project follows the western section of the original Northwestern Turnpike.