Its western terminus is at the Indiana state line near Willshire (the route continues as State Road 124), and its eastern terminus is at SR 53 in Patterson.

The route also goes through or close to the towns of Elgin, Lima, Ada, and Dunkirk.

It was originally routed from Ada to Patterson on the former northernmost section of the now-defunct SR 69.

[6][7] SR 81 was extended to the Indiana state line in 1940 along formerly unnumbered roads from Ada to Lima and along the route of the now-defunct SR 704 (which was created in 1937[8]) from Lima to the state line.

From 1923 to 1926, SR 81 was a short route in northeastern Ohio between Brentwood Lake and Twinsburg.