For much of its route, US 280 travels through rural areas and smaller cities in southern Georgia and east central Alabama.

US 280 is the main connector between Birmingham, AL and Auburn, AL, and this stretch is sometimes known as the “War Eagle Highway.“[2] Through Talladega County, Alabama, US 280 is known as the Jim Nabors Highway, in honor of the Sylacauga, Alabama, native known for portraying the television character Gomer Pyle.

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.

As a result, US 280 now bypasses numerous small towns in east Alabama, including Goodwater, Jackson's Gap, Camp Hill and Waverly.

In Georgia, US 280 from Columbus to I-16 is also a Governor's Road Improvement Program (GRIP) corridor known as "Power Alley".

[4] The route continues through one of the more developed areas of east Birmingham and eventually climbs over Double Oak Mountain into Shelby County and Chelsea.

The route continues south-east through northern Coosa County until it has another diamond interchange with SR 9.

It crosses into Tallapoosa County just before entering Alexander City, which is home to Russell Athletic.

It continues on a heavily traveled road into Russell County, and eventually to Phenix City, which is actually in the Eastern Time Zone due to its close proximity with Columbus, Georgia across the Chattahoochee River.

From here, US 280 continues on its own east, passing through Plains (the boyhood home of Jimmy Carter) and becomes cosigned with State Route 30 in Americus.