While most odd numbered Interstates run north–south, I-71 takes more of a northeast–southwest course, with some east–west sections, and is mainly a regional route serving Kentucky and Ohio.

Between Louisville and Cincinnati, I-71 is largely a four-lane highway, except for the approach to Kentucky Speedway in Sparta in which it runs three lanes each way for about two miles (3.2 km).

Near the town of Carrollton, there are signs marking the location of a tragic accident that occurred on May 14, 1988, when a drunk driver was driving north in the southbound lanes and struck a church bus full of children and teenagers, causing the bus's fuel tank to ignite into flames and killing 27 people on board.

I-71 then heads in a general northeast direction through the Lytle Tunnel and urban Cincinnati and into its surrounding suburbs.

It continues northeast until it reaches South Lebanon, where it begins cutting east across the flat plains of southwest Ohio.

After another interchange with the I-270 bypass, the highway exits Columbus and continues north until near Delaware, where it again turns northeast.

Beginning its path to Cleveland, I-71 enters the rolling farm country on the edges of the Allegheny Plateau.

It was planned to run from Cincinnati to Conneaut and connect with an extension built across the panhandle of Pennsylvania to the New York State Thruway.

Today, only two tracks cross the viaduct, and the rest of the structure supports a large, weedy field.

Between 2004 and 2006, the interchange at milepost 121 in the far northern reaches of Columbus was reconstructed to allow access to the eastern extension of Gemini Place.

The plans did not include widening the 25-mile (40 km) stretch in Delaware and Morrow counties, calling for patching that section instead.