It is part of the United States Numbered Highway System that travels from Perry in North Florida to Lynchburg in Central Virginia.

While in South Carolina, the highway travels through Greenwood, Laurens, Woodruff, and Spartanburg.

Almost instantly curves to the north but then to the east before seeming to terminate at South Carolina State Highway 28 in Clarks Hill, South Carolina (which is part of the Savannah River Scenic Byway[7]), but in reality turns left and joins the road in a concurrency.

US 221/SC 28 runs north and northwesterly often being flanked by a railroad line along the east side as it passes through Modoc where it encounters the Hamilton Branch State Park and Recreation Area, and later Parksville which contains the Parksville State Recreation Area.

After the intersection with Callison Road, and later two other local streets, SC 10 branches off to the northwest towards Verdery, and US 221 leaves the Sumter National Forest.

[6] From Greenwood, U.S. Route 221 continues northeasterly to the city of Coronaca and after crossing a bridge over the Saluda River the concurrency with SC 72 comes to an end.

After the truck route ends, it continues northeast and then northwest before the interchange with Interstate 385 in rural Laurens County.

It continues to the city of Chesnee before exiting the state in a rural area of Cherokee County.

Between 1968 and 1970, US 221 was rerouted onto the Greenwood Bypass and its current routing south of US 25/US 178, replacing the remaining part of SC 670.