State Route 251 or SR-251 is a 16-mile-long (26 km) route that serves as a connection U.S. Highway 31 in Athens with State Route 53 in Ardmore.

The northern terminus of SR-251 is located at its intersection with State Route 53 in downtown Ardmore. From this point, the route travels in a southeasterly direction to Pine Dale. From Pine Dale, the route resumes in a southerly direction before turning to the southwest near Pisgah. It continues in this direction until reaching its southern terminus at U.S. Highway 31 in Athens. SR-251's entire route was formerly designated as US-31 before that route overlapped I-65 between Athens and Ardmore.

The entire route is in Limestone County.