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. It passes through rural parts of Madison County and runs along the Madison-Hart County line before entering Franklin County. Almost immediately after crossing the county line, SR 281 meets its northern terminus, an intersection with SR 17 Business (Church Street) in Royston.