Its route is in Madison and Franklin Counties, with a brief section straddling the Madison-Hart County line.

SR 281 begins at an intersection with US 29/SR 8 (General Daniels Avenue North) northeast of Danielsville.

It heads northeast to an intersection with SR 191 (Dalton Drive).

The highway crosses the Broad River, and curves into a more north-northeast routing.

Almost immediately after crossing the county line, SR 281 meets its northern terminus, an intersection with SR 17 Business (Church Street) in Royston.