State Route 621 (SR 621) is a north–south state highway in the central part of the U.S. state of Ohio. The southern terminus of SR 621 is at U.S. Route 36 (US 36) approximately 2.50 miles (4.02 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.