U.S. Route 52 runs east–west across the southern part of the state of Ohio along the Ohio River, passing through or very near the cities and towns of Cincinnati, Portsmouth, and Ironton. For its first 19 miles (31 km) or so, the highway runs concurrently with Interstate 74 (I-74) and I-75 before it winds through downtown Cincinnati for several miles. The route is primarily two lanes between New Richmond and West Portsmouth, Ohio, where it becomes a four-lane partial access highway until it exits the state near Chesapeake.

Interstate 75 (I-75) runs from Cincinnati to Toledo by way of Dayton in the US state of Ohio. The highway enters the state running concurrently with I-71 from Kentucky on the Brent Spence Bridge over the Ohio River and into the Bluegrass region. I-75 continues along the Mill Creek Expressway northward to the Butler County line just north of I-275. From there, the freeway runs into the Miami Valley and then passes through the Great Black Swamp before crossing into Michigan.