U.S. Route 280 is a spur of U.S. Highway 80. It currently runs for 392 miles (631 km) from Blichton, Georgia at U.S. Highway 80 to Birmingham, Alabama at I-20/I-59. For much of its route, U.S. 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 U.S. 280 throughout northern Shelby County and southern Jefferson County.

Through Talladega County, Alabama, U.S. 280 is known as the Jim Nabors Highway, in honor of the Sylacauga, Alabama, native known to the world as Gomer Pyle. The historical designation of US-280 and SR-38 is the Florida Short Route.

For many years, US-280 and SR-38 was considered one of the more dangerous routes in Alabama, due to the number of large stretches of narrow two lane roadway leading southeastwardly from Birmingham. Work was completed in 2006 making U.S. 280 a four-lane highway throughout the entire state of Alabama. This project began in the 1970s. As a result, U.S. 280 now bypasses numerous small towns in east Alabama, including Goodwater, Jacksons' Gap, Camp Hill and Waverly.

In Georgia, US 280 from Columbus, Georgia to I-16, is also a GRIP corridor known as "Power Alley".

US 280 begins at an interchange with Interstate 20, Interstate 59, and U.S. Route 31 in downtown Birmingham. US 280 continues south, cosigned with US 31 along the Elton B. Stephens Expressway (locally known as the Red Mountain Expressway). The routes interchange with U.S. Route 11 and U.S. Route 78 prior to exiting the city. At Homewood, the expressway comes to an end as US 280 separates from US 31. In Cahaba Heights, US 280 interchanges with Interstate 459.

US 280 is paired with unsigned State Route 38 throughout the state. The U.S. Highway has a length of 141.356 miles (227.490 km) in Alabama.

US 280 begins in Georgia at the state's border with Alabama in Columbus. There it is paired with State Route 520 and U.S. Route 27. It maintains this designation as it passes through Fort Benning. US 280 continues east, where it passes through Plains (the boyhood home of Jimmy Carter) and becomes cosigned State Route 30 in Americus. It maintains this designation until the route's terminus in Blichton.

Prior to the completion of the Elton B. Stephens (Red Mountain) Expressway in Birmingham, U.S. 31, U.S. 78 and U.S. 280 overlapped until they junctioned U.S. Route 11 at the intersection of 1st Avenue North and 24th Street.