Ohio State Route 278 is mainly a north-south route in areas west of Athens, Ohio. This route connects Zaleski, Nelsonville, and points just north of Nelsonville. The northern end is at Ohio Route 595, south of New Straitsville. Ohio Route 278 runs southeast from there to Nelsonville, crossing under US Route 33 with no interchange. (A short business route for US Route 33 runs through Nelsonville, which can be used to connect to the mainline of US Route 33.) Ohio Route 278 continues westerly and southerly from Nelsonville to Ohio Route 677 in Zaleski. Past Zaleski, the route continues just a little further south to US Route 50, in east-central Vinton County. This junction with US Route 50 is the southern terminus of Ohio Route 278.