State Route 51 is a 115-mile (185 km) long route in the southeastern and east-central part of the state. The southern terminus of the route is at its junction with U.S. Highway 84 near New Brockton. The northern terminus of the route is at an interchange with Interstate 85 and U.S. Highways 29 and 280 at Opelika.

While it is signed as a north–south route, the orientation of State Route 51 is rather irregular. From its beginning near New Brockton, the route heads in a northeasterly direction, passing through rural areas and small towns in the southeastern part of the state.

State Route 51 passes through Clio, the birthplace of former Alabama governor George C. Wallace and Baseball Hall of Fame member Don Sutton. At Clio, the route turns briefly turns northward, then resumes its northward trajectory as it leads towards Clayton. At Clayton, the route then turns northwestward then northward as it leads towards Midway.

At Midway, State Route 51 joins U.S. Highway 82 and turns westward. The concurrency of the two routes ends east of Union Springs. State Route 51 then resumes a northeastward trajectory until it approaches Hurtsboro. The route then turns northward, continuing this orientation until it reaches its terminus at Opelika.

When State Route 51 was created in 1940, it covered only the route between Clayton and Midway. The route was extended to its current southern terminus in 1957, and was extended to its current northern terminus in 1986.