The Sandusky River rises in Crawford County just northeast of Galion. It flows about 10 miles in a northwesterly direction before turning to the west-southwest running through Bucyrus. It then turns to the west and then north flowing through Upper Sandusky and is joined by its major tributary, Honey Creek, just south of Tiffin. The river continues north flowing through Fremont before emptying into Sandusky Bay.

A section of the river was the second in the state to be designated as "scenic". The section is located in the northwestern agricultural section of Ohio between Upper Sandusky and Fremont and features exposed limestone and dolomite outcroppings.