State Route 21 is a 278-mile (447 km) state highway that extends from Piedmont in Calhoun County to the Florida state line near Atmore in Escambia County. The route runs almost the entire length of the state from the northeast to the southwest. It is the longest signed state route in Alabama.

Starting at a junction with SR-9 in Piedmont, the route runs southwest through Anniston, Talledega and Sylacauga. The route passes close to the Talladega Superspeedway and the Talladega National Forest. After Sylacauga the road is co-routed with U.S. Highway 231 as it heads almost directly south towards the state capital, Montgomery. Southeastroads.com gives this opinion on the part of the highway through Montgomery:

The highway is co-routed with U.S. Highways 82 and 80 around the Montgomery city center, then diverges southwest of the city. The route proceeds through Oak Hill and Beatrice to Monroeville in Monroe County, and is co-routed with SR-47 for part of this section. The route then runs continued southwest through Frisco City and Atmore to the Florida state border, where the road becomes Florida SR-97. The route is paved throughout and often multi-lane. Counties traversed by the route include Calhoun, Talladega, Coosa, Elmore, Montgomery, Lowndes, Wilcox, Monroe and Escambia.