U.S. Route 221 (US 221) in the U.S. state of Georgia is a south–north U.S. Highway. It travels from the Florida border near the Quitman area to the South Carolina state line, north of . The highway connects North Central Florida with Upstate South Carolina. Concurrencies of US 221 with U.S. Highways in Georgia include US 84 from Quitman to Valdosta, US 41 in Valdosta, US 129 in the vicinity of Lakeland, US 441 from south-southwest of Pearson to Douglas, part of US 23/US 341 in Hazlehurst, US 319 within the vicinity of Bartow, and US 1 from Louisville to Wrens.