U.S. Route 221 Truck (US 221 Truck) directs truck drivers away from the local streets of Hazlehurst, Georgia, including the one-way pair section of US 221. It begins on East Jefferson Street from US 221 which is shared with US BUS 23/GA 135 Connector. When US BUS 23/SR Conn 135 ends at US 23/SR 19, US Truck 221/GA Truck 135 turn left onto the US 23/SR 19 overlap known as Larry Contos Boulevard, and then turns left onto US 341/SR 27 (Golden Isles Parkway) eventually terminating at northbound US 221 and the north end of US BUS 23. The route is entirely overlapped by Georgia Truck Route 135.
U.S. Route 221 Business (US 221 Bus), established in 1991, is a 5-mile (8.0 km) business loop through downtown Marion, via Main Street. It follows the old US 221 alignment before it was rerouted onto Marion Bypass, located west of the city. It also shares a partial overlap with US 70 north of the city center area.
U.S. Route 221 Truck (US 221 Truck) provides an alternate route for truck drivers between Linville and Boone, via NC 105. It avoids an 18-mile (29 km) drive of endless curves and constant elevation changes along a stretch of US 221 between Linville and Blowing Rock, dubbed the Little Parkway Scenic Byway. In Boone, the truck route overlaps with US 321 Truck and US 421 Truck.
U.S. Route 221 Business (US 221 Bus), established in November, 1981, is a 4.4-mile (7.1 km) business loop through West Jefferson (via Jefferson Avenue and Second Street) and Jefferson (via Main Street). Sharing partial overlaps with NC 194 and NC 88, it follows the original US 221 alignment before it was rerouted onto new bypass route east of the towns in September, 1981.