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. It continues to the northeast into Gray Township where it veers to the southeast toward the village of Rogersville in Center Township. Just before reaching Rogersville, Route 21 merges with Pennsylvania Route 18 near West Greene High School. Route 18 leaves Route 21 near West Waynesburg while Route 21 continues into the borough of Waynesburg.^[2]

In Waynesburg, PA 21 is a one-way pair as High Street (west) and Greene Street (east). Both streets are two lanes in the borough. High Street is the arterial road through Waynesburg's business district. While in Waynesburg, it shares its route with U.S. Route 19. PA 21 leaves Waynesburg entering the census-designated place of Morrisville. PA 21 becomes a two-lane road with a shared left turn lane for less than a mile before US 19 leaves the route and PA 21 stays east, becoming a four lane divided highway. Interstate 79 exit 14 is PA 21 in Morrisville signed for PA 21 to Masontown and Waynesburg. PA 21 then leaves Morrisville in Jefferson Township.^[3]

PA 21 travels east-southeast through the rest of rural Greene County. The road is mostly level and the countryside is mostly farmland. 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.^[4]

PA 21 enters Fayette County in the borough of Masontown. It bypasses Masontown to the north and merges with PA 166 (Main St.). 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.^[5] The highway enters South Union Township in the village of Uledi. It intersects Dixon Boulevard before entering the city of Uniontown. It has an interchange with U.S. Route 40/U.S. Route 119 near Cherry Tree Square. It passes the Uniontown Hospital before ending at US Route 40 Business (Main St.).^[6]

In 1911, what would become PA 21 was designated as part of Legislative Route 256 between the West Virginia border and Rogersville, Legislative Route 111 between Rogersville and Waynesburg, and Legislative Route 112 between Waynesburg and Uniontown.^[7] PA 21 was designated in 1927 to run from the West Virginia border east to US 40 in Uniontown. The route followed its current alignment to west of Carmichaels, where it headed east by way of Carmichaels and New Salem to Uniontown. The alignment utilized a ferry across the Monongahela River.^[8][9] By the time of its inception, PA 21 existed as a paved road between Wind Ridge and PA 121 east of Waynesburg, in the Carmichaels area, and from south of Republic to Uniontown.^[9] The remainder of PA 21 was paved by 1940.^[10] By 1950, PA 21 was rerouted to follow PA 88 between Carmichaels and Paisley, where it turned east and crossed the Monongahela River at Masontown and followed its current alignment to Uniontown.^[11] Bypasses of Carmichaels and Masontown were built by 1960. Also by this time, PA 21 was widened into a divided highway near the PA 88 intersection in Paisley,^[12] By 1970, a portion of PA 21 east of Waynesburg was converted to a divided highway.^[13] A new, four-lane Masontown Bridge over the Monongahela River was completed in 2015. It replaced the two-lane bridge built in 1925.^[14]

•   U.S. Roads portal
•   Pennsylvania portal
• List of crossings of the Monongahela River

• Pennsylvania Highways: PA 21