 PA 21 was originally designated in 1927 between the West Virginia border and Uniontown, originally following an alignment further to the north between Carmichaels and Uniontown via New Salem.By 1950, the route was moved to its current alignment east of Carmichaels, with bypasses of Carmichaels and Masontown constructed by 1960.Pennsylvania Route 21 enters Greene County in Richhill Township near the village of Polen.