Pennsylvania Route 21 (PA 21) is a 50.5-mile (81.3 km) long east–west state highway in the US state of Pennsylvania. The western terminus of the route is at the West Virginia state line in Richhill Township, where PA 21 continues into West Virginia as West Virginia Route 891. The eastern terminus is at U.S. Route 40 Business in Uniontown. The route is known as the Roy E. Furman Highway for most of its length.

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.

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.

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 with Pennsylvania Route 88 at a busy intersection, then becomes a four-lane divided highway until it reaches Hatfield Ferry Power Station and the Masontown Bridge over the Monongahela River.

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.

The highway enters South Union Township in the village of Uledi. It intersects with 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 also passes Fayette County's main shopping district and Uniontown Hospital before ending at US Route 40 Business (Main St.).

Pennsylvania Route 21 was first signed in 1928. It was first paved from the West Virginia state line to Ryerson in 1929. Originally, the highway was routed to Carmichaels. In 1953, it was realigned onto its current route from George St. in Cumberland Township to Uniontown. PA 21 has been widened several times and several medians have been installed due to increased use since the 1950s. Improvements, including a new bridge over the Monongahela River, are in the plans for the future.