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.

US 50 intersects US 119 in the eastern part of the city before continuing east through Thornton and curving through the mountains to Evansville.

After passing through Gormania, the highway continues through the forest, and runs concurrently with Route 42 from near Mount Storm to near Hartmansville.

US 50 continues east through Hanging Rock and Loom, crossing the Cacapon River in Capon Bridge.