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.

After I-275 branches due northeast, both US 52 and I-74 then meet Rybolt Road/Harrison Avenue and North Bend Road; all are partial cloverleaf interchanges.

Less than a mile after that, I-74 ends as they meet I-75 west of the Cincinnati State Technical and Community College.

Then, they also briefly travel east along that street before intersecting US 127 (Central Parkway) at a one-quadrant interchange.

Then, up until the Cincinnati Municipal Airport Lunken Field, US 52 is sandwiched between US 50 up north and the river down south.

In downtown Aberdeen, US 52 intersects SR 41 and then the Simon Kenton Memorial Bridge.

[2] On its way towards the West Huntington Bridge, US 52 meets more state routes in different locations, including SR 823 in Sciotodale.

East of Burlington, US 52 then turns south towards the bridge, crossing the Ohio River and the West Virginia state line.