US 220 narrows to two lanes north of Roanoke, connecting to I-64 near Clifton Forge and then paralleling the Appalachian Mountains north-northeasterly in the direction of Cumberland, Maryland.

From the state line to Roanoke, US 220 is a four-lane mix of freeway bypasses and 55 miles per hour (89 km/h)[citation needed] at-grade rural highway.

[3] US 220 meets the northern terminus of State Route 87 in Ridgeway, and soon after turns west to bypass the city of Martinsville on a freeway partially shared with US 58.

This is repeated several times until Forks of Waters, where the South Branch Potomac River enters US 220's valley and parallels its final 1 mile (1.6 km) to the state line.

Otherwise the gaps were filled starting in 1922, with the legislative designation of a spur of SR 14 from Clifton Forge south to Eagle Rock, which was numbered State Route 142 in 1923.

The first piece of State Route 395, which ended up extending from Warm Springs to West Virginia, was also created in 1924 as a spur from SR 39 at Monterey.