US 84 enters the state from Mississippi west of Silas and exits into Georgia southeast of Gordon.

Along its route, US 84 passes through the limits of the towns and cities of Silas, Coffeeville, Grove Hill, Repton, Evergreen, River Falls, Andalusia, Sanford, Babbie, Opp, Elba, New Brockton, Enterprise, Level Plains, Daleville, Dothan, Cowarts, Avon, Ashford.

Between Mississippi and River Falls, with the exception of a small segment near Grove Hill, US 84 is largely a rural two-lane road.

For most of its route through Alabama, excluding a section in Dothan where it is alternatively known as East and West Main Street, US 84 is internally designated by the state of Alabama as State Route 12 (SR 12).

When U.S. Route 84 was initially designated in 1926, its western terminus was located in Dothan.