U.S. Route 280 is a spur of U.S. Highway 80. It currently runs for 392 miles (631 km) from Blitchton, Georgia, at US 80 to Birmingham, Alabama at I-20/I-59. For much of its route, US 280 travels through rural areas and smaller cities in southern Georgia and east central Alabama. Once the highway approaches Birmingham, it is a major suburban route. Numerous shopping centers are located on US 280 throughout northern Shelby County and southern Jefferson County.

Birmingham is a city in the north central region of Alabama. Birmingham is the county seat of Jefferson County, Alabama's most populous county. As of the 2022 census estimates, Birmingham had a population of 196,910, down 2% from the 2020 census, making it Alabama's third-most populous city after Huntsville and Montgomery. The broader Birmingham metropolitan area had a 2020 population of 1,115,289, and is the largest metropolitan area in Alabama as well as the 50th-most populous in the United States. Birmingham serves as an important regional hub and is associated with the Deep South, Piedmont, and Appalachian regions of the nation.