The southern terminus of SR 621 is at U.S. Route 36 (US 36) approximately two and a half miles (4.0 km) northeast of Coshocton, and its northern terminus is adjacent to the North Appalachian Experimental Watershed Station, just north of its intersection with White Eyes Township Road 188, about 5 miles (8.0 km) northwest of the hamlet of Fresno.

Continuing north after SR 621 ends is County Road 190 (CR 190).

Established in the early 1940s, SR 621 is a two-lane spur route whose primary purpose is to provide access to the North Appalachian Experimental Watershed Station from the state highway network.

[5] SR 621 starts at an intersection with US 36 and CR 621 near the community of Canal Lewisville, with a sign saying "North Appalachian Experimental Watershed" along US 36.

Part of this re-routing resulted in the southern terminus of SR 621 being moved to its present location at US 36 northeast of Coshocton.