The highway begins near Pocahontas and runs north to the Missouri state line.

The route is maintained by the Arkansas Department of Transportation (ArDOT).

[3] Highway 251 begins north of Pocahontas in Randolph County in a transition zone between the Arkansas Delta and Ozark Mountains.

Highway 251 serves as a terminus for two minor state highways on the path north, and passes near the Robert L. Hankins Mud Creek Wildlife Management Area.

[5] It started at Highway 115 and ran north for 12 miles (19 km) toward Warm Springs.