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.

From there, the freeway runs into the Miami Valley and then passes through the Great Black Swamp before crossing into Michigan.

The Mill Creek Expressway is a heavily trafficked portion of I-75 in Ohio, from the Ohio River at the Kentucky state line to Butler County in Cincinnati's northern suburbs that follows the path of its namesake, Mill Creek, and the former path of the Miami and Erie Canal, and passes through the city's industrial core.

The highway then intersects the Cincinnati beltway, I-275, and continues northeasterly through the West Chester Township, Monroe, Middletown, and Franklin en route to the Dayton metropolitan area.

The highway then continues north through the western side of the state toward Toledo, passing through the small cities of Troy, Piqua, Lima, Findlay, and Bowling Green.

Work began in May 2019 to convert the existing interchange with Union Centre Boulevard in West Chester Township, Butler County, to a DDI.

The canal extended from the Ohio River along the present locations of Eggleston Avenue and Central Parkway to Mount Storm Park and continued north, remaining close to the Mill Creek Expressway to Butler County.

The first portion of the expressway was built by the Works Progress Administration (WPA) in 1941[a]—during World War II—to serve the Wright Aeronautical plant in Lockland.

[citation needed] A short extension was built south to Towne Street in Elmwood Place in the late 1940s.

[citation needed] In 1960, plans were announced to add an eastern portion that would result in Arlington Heights being surrounded on both sides by the highway.

[19] The span that failed was the segment of the former northbound ramp to Hopple Street that passed over the southbound lanes of I-75.

[24][needs update] In Cincinnati, approximately 17 miles (27 km) of the highway will be totally reconfigured by three separate ODOT projects happening simultaneously.

The southernmost is I-275, which serves as a full loop around Cincinnati, including segments that extend into Indiana and Kentucky.