Its western terminus is within the Cincinnati city limits, about 5 miles (8.0 km) east of downtown, at U.S. Route 50 – this is also the western terminus of State Route 32 and the southern terminus of State Route 561.

Heading east from the Cincinnati neighborhoods of Mount Lookout, Linwood, and Mount Washington, State Route 125 passes through numerous subdivisions in Anderson Township as a four lane road, Beechmont Avenue.

After the Clermont County line, State Route 125 becomes Ohio Pike, the old Ohio Turnpike, originally built in 1831 by E.G. Penn,[2] not related to the modern highway of the same name.

Passing under Interstate 275, State Route 125 begins to lose its suburban feel after the villages of Amelia and Hamlet as it heads into the countryside of eastern Clermont, Brown, Adams, and Scioto Counties.

This section of State Route 125 is part of the Scenic Scioto Heritage Trail.