It runs from the Red River (where it crosses into Texas as State Highway 78) to Tishomingo.

Near Yuba, SH-78 curves west to head toward Achille, where it meets State Highway 91.

It curves back north here, meets State Highway 70E, and then passes through the east part of Durant, where it crosses US-70.

It then meets SH-22 for a second time three miles (5 km) east of Tishomingo.

SH-78 was originally designated as a route from Boise City to the Texas Border.