SR 646 begins at a stop-controlled intersection with US 250 in Stock Township, Harrison County; about 8 miles (13 km) northwest of Cadiz.

The state route heads northeast towards Scio through a valley formed by a small creek.

Once it reaches Scio, the route makes numerous turns, has a grade crossing with an Ohio Central Railroad and the Conotton Creek Trail, and shares a brief concurrency with SR 151.

The route heads through the hills of Appalachia passing through the villages of New Rumley, the birthplace of General George Armstrong Custer, and Germano.

The route gradually heads southeast towards Wintersville and ends at SR 43, 0.09 miles (140 m) north of the Wintersville village limits and 0.3 miles (0.48 km) north of an interchange with US 22.