State Route 104 (SR 104) is a north–south highway in Southern Ohio. Its southern terminus is at U.S. Route 23 in Portsmouth, Ohio and its northern terminus is at U.S. Route 33 in Columbus. The route passes through or close to the towns of Portsmouth, West Portsmouth, Coles Park, Waverly, Chillicothe, Grove City, and Columbus. From Waverly to Chillicothe, it overlaps U.S. Route 23.

State Route 104 is an original state highway with two parts: One from Portsmouth to Waverly, and one from Chillicothe to Columbus. The southern part of the route was decertified when U.S. Route 23 was certified in 1926. This southern route was replaced with the now defunct route number State Route 112. In 1952, the southern part of the route was recertified as State Route 104, connecting to the northern part of the route by overlapping U.S. Route 23. The route close to Portsmouth was concurrent with State Route 73. Since 1968 the northern terminus has been extended twice – to U.S. Route 23 in 1968 and to U.S. Route 33 via freeway in 1989 – and its southern terminus has been extended twice into Portsmouth in 1972 and to U.S. Route 23 in 1974.

As of 2010, part of State Route 104 right outside of Chillicothe in Ross County has been converted into a four lane.