It continues through the city of Perry and intersects Interstate 10 and U.S. Route 90 in rural Madison County before crossing into Georgia.

U.S. Route 221 runs through the cities of Quitman, Valdosta, Lakeland, Pearson, and Douglas in southern Georgia.

U.S. Route 221 enters South Carolina in rural McCormick County at the southeastern edge of Lake Strom Thurmond.

From Greenwood, U.S. Route 221 continues northeasterly to the city of Waterloo, South Carolina.

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

It runs through the cities and towns of Rutherfordton, Marion, Blowing Rock, Boone, and Jefferson.

The highway is predominantly two-lane, while four-lane in Marion, Blowing Rock, and Boone.