U.S. Route 221 (US 221) is a part of the U.S. Highway System that runs from Perry, Florida to Lynchburg, Virginia. In Virginia, the U.S. Highway 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 east–west 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.
US 221 enters Grayson County, Virginia from North Carolina concurrent with US 21. The U.S. Highways follow two-lane New River Parkway, which crosses the New River a short distance north of the state line. US 221 and US 21 enter the town of Independence as Independence Avenue, which intersects US 58 (Main Street) in the center of town. US 21 continues north on Independence Avenue toward Wytheville while US 221 turns east onto Main Street. US 221 and US 58 exit the town as Grayson Parkway, which expands to a four-lane divided highway just west of its intersection with SR 274 (Riverside Drive). The U.S. Highways parallel the New River for a short distance before crossing the river at one of its bends. US 221 and US 58 pass to the north of the community of Baywood before meeting the southern end of SR 94 (Riverside Drive).
U.S. Route 221 is a spur of U.S. Route 21. It runs for 734 miles (1,181 km) from Perry, Florida at U.S. Routes 19/98/27 Alternate to Lynchburg, Virginia at U.S. Route 29 (Lynchburg Expressway). It passes through the states of Florida, Georgia, South Carolina, North Carolina, and Virginia. It goes through the cities of Valdosta, Georgia, Spartanburg, South Carolina, Roanoke, Virginia, and Lynchburg, Virginia.
Throughout western North Carolina from the Virginia border to the Blue Ridge Parkway, U.S. 221 is a challenging drive, and can be described as one climb after another. There are few places where the road builders attempted to skirt around large foothills.
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.
U.S. Route 221 (US 221) in Florida is a north–south United States Highway. It runs 40 miles (64 km) from Perry northwest to the Georgia State Line in Taylor, Madison and Jefferson Counties. The entire route is inventoried by FDOT as the northern section of unsigned State Road 55. A short overlap with US 90 exists in Greenville.
U.S. Route 221 begins in the City of Perry at the intersection of US 19-98-Alt 27 at the northern terminus of CR 361A. US Truck Route 221 also begins at this intersection, but runs along US 19-98-ALT 27. North of the terminus of CR 335, the road narrows down to two lanes at the intersection of US 27, which includes another leg of the truck detour. North of US 27, Route 221 crosses a bridge over Spring Creek and then meets a pair of at-grade crossings with railroad line owned by Georgia and Florida Railroad, which leads to a branch of the Georgia Southern and Florida Railway further north. Nearby it passes by a former Live Oak, Perry and Gulf Railroad station and then the Perry City Hall, and more than several blocks north of that point crosses another bridge over Pimple Creek just south of the intersection of County Road 356 (Ash Street). Intersections north of the city limits include County Road 359A, which is also the northern terminus of US Truck Route 221, and later County Road 361. The aforementioned G&F Railroad line meets up with the west side of US 221, but runs parallel with it throughout Taylor County, even as they both approach CR 14 (an extension of SR 14) in Shady Grove.
U.S. Route 221 in North Carolina runs north–south from the South Carolina state line to the Virginia state line in Western North Carolina.
US 221 enters from South Carolina as a rural highway, with mostly farms, wooded areas, or homes dotting the road. After 10 miles (16 km) it connects with US 74, where US 74 Business begins its overlap towards Rutherfordton (signs of US 74 Business are scarce throughout). At Rutherfordton, the first major intersection is Charlotte Street, where US 74 Business and US 221 Alternate go east. After Rutherfordton, the road reverts to a rural highway, and continues on to Marion.
Before entering Marion city limits, Interstate 40 intersects with US 221. US 221 then joins with NC 226, going west around the city on the Marion Bypass. After the expressway passes the shopping centers along US 70, it continues as a 4-lane highway with a turning median all the way to North Cove. Along the way, several business can be seen including shrubbery farms, stone/rock cutters, and a chemical plant. NC 226 splits early at Woodlawn, for travelers that want to go to Spruce Pine.