The western terminus of SR 781 is at SR 41 about 2+1⁄2 miles (4.0 km) southwest of Peebles in the unincorporated community of Jacksonville.

Its eastern terminus is eleven miles (18 km) to the southeast at a T-intersection with SR 348, which is approximately five miles (8.0 km) northeast of the community of Wamsley.

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

All of SR 781 is located within the eastern portion of Adams County.

The route has not experienced any changes of major significance since it first appeared.