U.S. Route 220 (US 220) is a U.S. Highway that travels from Rockingham, North Carolina, to South Waverly, Pennsylvania.

The highway enters West Virginia two miles (3.2 km) south of Harper in Pendleton County.

The highway enters Grant County approximately 17 miles (27 km) north of Franklin.

At the top of Knobly Mountain northwest of Ridgeville, US 220 splits from US 50 and resumes a northerly alignment as it descends into the New Creek Valley.

At the northern edge of Keyser, US 220 crosses the North Branch Potomac River via Memorial Bridge, leaving West Virginia and entering Maryland.