State Route 781 (SR 781, OH 781) is an east–west state highway in southern Ohio, a U.S. state. The western terminus of State Route 781 is at State Route 41 about 2.5 miles (4.0 km) southwest of Peebles. Its eastern terminus is 11 miles (18 km) to the southeast at a T-intersection with State Route 348, which is approximately 5 miles (8.0 km) northeast of the unincorporated community of Blue Creek.

Created in the late 1930s and existing entirely within Adams County, State Route 781 passes through rough terrain and by Peach Mountain, which rises over 1,200 feet (370 m).

All of State Route 781 is located within the eastern portion of Adams County. The highway is not inclusive within the National Highway System.

State Route 781 debuted in 1938 along the routing between State Route 41 and State Route 348 that it occupies to this day. The route has not experienced any changes of major significance since it first appeared.

The entire route is in Adams County.