State Route 21 (SR 21) is a 279-mile (449 km) state highway that extends from the Florida state line, near Atmore in Escambia County to Piedmont in Calhoun County. The route travels almost the entire length of the state from the northeast to the southwest. It is the longest signed state route in Alabama.

Escambia County is a county located in the south central portion of the U.S. state of Alabama. As of the 2020 census, the population was 36,757. Its county seat is Brewton.