Pennsylvania Route 21 enters Greene County in Richhill Township near the village of Polen.

The highway winds its way through the hilly and sparsely populated area passing Ryerson Station State Park to the north.

PA 21 leaves Waynesburg entering the census-designated place of Morrisville.

[3] PA 21 travels east-southeast through the rest of rural Greene County.

In Paisley, PA 21 intersects Pennsylvania Route 88, then becomes a four-lane divided highway until it crosses the Masontown Bridge over the Monongahela River.

After leaving Masontown, the southernmost point on the route, PA 21 becomes McClellandtown Road.

It turns to the northeast entering German Township and leaving PA 166.

Passing through McClellandtown, PA 21 traverses more densely populated western Fayette County entering South Union Township.

[7] PA 21 was designated in 1927 to run from the West Virginia border east to US 40 in Uniontown.