From Chesnee, South Carolina to Independence, Virginia, it connects the cities of Rutherfordton, Marion, Boone and Jefferson between the two out-of-state destinations.

US 221 enters from South Carolina as a rural superstreet highway, with mostly farms, wooded areas, or homes dotting the road.

NC 226 splits at Woodlawn, for travelers that want to go to Spruce Pine while US 221 continues as a divided highway to Pitts Station Road at North Cove.

At Linville, motorists are recommended to follow NC 105/US 221 Truck to Boone and Blowing Rock, which is faster and flatter.

[2] The entrance to Grandfather Mountain is located near Linville; also nearby is the Linn Cove Viaduct, via the Blue Ridge Parkway.

Blowing Rock and Boone are popular year-round tourist destinations; as such the highway between the two towns offers an array of activities include skiing, shopping, amusement rides, and golf.

The next 21 miles (34 km) of US 221 is very curvy, similar to the stretch between Linville and Blowing Rock (minus the continuous elevation changes).

[11] Around 1953, US 221 was rerouted between Boone and Baldwin, by linking with US 421 to Deep Gap then north on new construction; the old alignment through Todd became an extension of NC 194.

[19] In 2005, US 221/US 421 was placed on new four-lane expressway between the South Fork New River and Deep Gap; its old alignment, which partially paralleled the Blue Ridge Parkway, was downgraded to secondary roads.

[11] In the Rutherfordton area, NCDOT is constructing an approximately 8.5-mile (13.7 km) four-lane freeway bypass to the east of downtown between US 74 to the south and Roper Loop Road in the north.

The project is part of a larger plan by NCDOT to convert US 221 between the South Carolina state line and I-40 near Marion to a four-lane divided highway.