The highway connects mostly rural areas of Hopkins County with Madisonville.

KY 281 begins at an intersection with U.S. Route 41 (US 41; North Main Street) in Madisonville, within Hopkins, where the roadway continues as US 41 Alt.

It travels to the northeast and crosses over some CSX railroad tracks.

Right after it leaves the city limits of Madisonville, it intersects the western terminus of KY 2281 (Carriage Lane).

The highway crosses over Elk Creek and intersects the western terminus of KY 2338 (Carroll Gentry Road).