Along its path through Ohio, I-70 passes through the following counties: Preble, Montgomery, Clark, Madison, Franklin, Fairfield, Licking, Muskingum, Guernsey, and Belmont.

[2] The portion of I-70 between I-675 and Enon Road in Clark County is designated as the "Deputy Suzanne Hopper Memorial Highway",[3] in honor of a Clark County Sheriff's deputy who was shot and killed on January 1, 2011, while responding to reports of gunshots at a mobile home park on Enon Road, near I-70.

After brief exits just outside the towns of Summerford and West Jefferson, I-70 reaches the southern part of Hilliard, where I-70 makes its first junction with I-270, a ring road around the Columbus area primarily serving its suburbs.

Once I-70 passes outside of Zanesville, the road connects with Norwich and New Concord, the latter of which also includes Muskingum University and the John and Annie Glenn Museum.

In St. Clairsville, I-70 connects with the Ohio Valley Mall and is less than 10 miles (16 km) from Wheeling, West Virginia.

I-70 appeared on the original American Association of State Highway and Transportation Officials (AASHTO) interstate route numbering map from August 14, 1957.

It was envisioned as a modern upgrade of the old National Road (US 40), the main east–west route through the heart of the state, built closely parallel to, but on a separate alignment from, the then overburdened and obsolete highway.

At that time, the highway was accessed at both ends via temporary at-grade intersections with the old National Pike, with I-70 and US 40 sharing the same carriageways.