PA 281 begins at the West Virginia border in Henry Clay Township, Fayette County, where the road continues into that state as WV 26.

PA 281 curves to the east and crosses into the borough of Markleysburg, where state maintenance begins[1] and it heads into residential areas.

PA 281 turns north-northeast onto Main Street where it passes more homes before heading back into Henry Clay Township and continues through woodland with a few small fields and residences.

At this point, PA 281 turns north to form a concurrency with that route on Oden Street, passing residences.

The route heads past businesses before turning northeast onto Park Street and passing under CSX's Keystone Subdivision railroad line.

The road turns east and crosses Laurel Hill Creek, passing between woods to the north and fields to the south as it enters Lower Turkeyfoot Township.

The route winds through a mix of farmland and woodland with some homes as it runs a short distance to the north of the CSX railroad line, passing through Brook.

PA 281 continues into Upper Turkeyfoot Township and heads away from the railroad tracks, running through open agricultural areas with some woods and homes as it goes through Paddytown.