The southern terminus of SR 251 is located at an intersection with US 31 opposite Pryor Street in Athens.

After crossing I-65 via overpass and exiting the Athens city limits, the route proceeds primarily northeasterly through several unincorporated communities before entering the city limits of Ardmore.

The northern terminus is located at an intersection with SR 53 running concurrently with 6th Street.

SR 251's entire route was formerly designated as part of US 31 between 1925[2] and 1956[3] before it was rerouted onto the corridor of present-day I-65, which it has overlapped on that particular stretch since 1966.

[4] The entire route is in Limestone County.