Florida

A US 221 shield used in Florida prior to 1993

U.S. Route 221 originates just south of the city of Perry, with its southern terminus intersecting with the cosigned U.S. Route 19 U.S. Route 98 and U.S. Route 27 Alternate, taking hidden SR 55 with it away from US 19. It continues through the city of Perry and intersects Interstate 10 and U.S. Route 90 in rural Madison County before crossing into Georgia.

Georgia

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

In Quitman, it joins U.S. Route 84 (cosigned Georgia State Route 38) to Valdosta. From Valdosta to Douglas, it joins with Georgia State Route 31. It also joins with Georgia State Route 135 and State Route 56. From Pearson to Douglas, it joins with U.S. Route 441 as a four-lane highway, which was completed in 2000.

In Douglas, U.S. Route 221 runs as the eastern part of Bowens Mill Rd. and will be widened in the future. It passes through Hazelhurst, Mount Vernon and Soperton before crossing Interstate 16, then later joins up with U.S. Route 1 and Georgia State Route 4 after passing through Louisville. After going through Wrens, it splits off to the north, cosigned with Georgia State Route 47 and passes through Harlem before crossing Interstate 20 /Georgia State Route 402 approximately 20 miles west of Augusta. Shortly before crossing into South Carolina, Georgia State Route 150 merges with Route 221 at the Pollards Corner intersection as Georgia 47 turns away. The passage into South Carolina takes place on top of the J. Strom Thurmond Dam, which forms the southern shore of Lake Strom Thurmond.

South Carolina

U.S. Route 221 enters South Carolina in rural McCormick County at the southeastern edge of Lake Strom Thurmond. It continues north and northwestward to the town of McCormick. From McCormick, it continues northerly to the city of Greenwood.

From Greenwood, U.S. Route 221 continues northeasterly to the city of Waterloo, South Carolina. U.S. Truck Route 221 bypasses the city of Laurens on the east side. It continues northerly and intersects Interstate 385 in rural Laurens County and proceeds to intersect Interstate 26 in rural Spartanburg County.

U.S. Route 221 continues through the center of the city of Spartanburg before intersecting Interstate 85 just north of the city. It continues to the city of Chesnee before exiting the state in a rural area of Cherokee County. The southern terminus of U.S. Alternate Route 221 intersects the main route in the city of Chesnee and exits the state a few miles to the east of the main route.

North Carolina

US 221 is a major highway in Western North Carolina. 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. The section from the U.S. Route 321 interchange just east of Boone and into Jefferson in Ashe county is now a divided, four-lane controlled-access road, making this section a much more pleasant and scenic one. Two sections of the highway can be considered challenging and twisty: 13-mile stretch between Linville and Blowing Rock, and a 21-mile stretch between Jefferson and Twin Oaks.

U.S. Route 221 has one Alternate (continuing from South Carolina) and two Business Routes (in Marion and Jefferson). It intersects two major highways: U.S. Route 74 near Rutherfordton and I-40 near Marion; and also intersects with the Blue Ridge Parkway four times.

Virginia

View north along US 221 at SR 615 just north of Floyd, Virginia

In Virginia, US 221 runs 149.61 miles (240.77 km) from the North Carolina state line near Independence north to its northern terminus at US 29 Business, US 460 Business, and US 501 Business in Lynchburg. US 221 connects Independence, Galax, and Hillsville in Southwest Virginia while running concurrently with US 58. The U.S. Highway connects those communities with Roanoke via Floyd County, within which US 221 is the main west–east highway. The U.S. Highway also runs concurrently with US 460 from Roanoke to Bedford and parallels that U.S. Highway from Bedford to Lynchburg.