Western Ohio

I-70's first exit within Ohio is in New Westerville, just south of New Paris. The exit is only accessible eastbound, and traffic going on to I-70 using the exit-only enters westbound lanes. I-70 goes on to pass Gettysburg before making two exits near Lewisburg, one at a junction with US 127 and another near downtown Lewisburg. I-70 also makes an exit in Brookville and runs concurrent with State Route 49 (SH 49) for just under 1.5 miles (2.4 km) before SH 49 continues to the southeast.

At this point, I-70 comes its closest to Dayton and primarily serves rural suburbs. Within the northern Dayton section of I-70, a separate series of ramps serves traffic to Dayton International Airport before entering a major intersection with I-75 just south of Vandalia. From there, I-70 continues to serve northern Dayton suburbs and also junctions the SH 4 expressway, which runs concurrent with I-70 between Wright-Patterson Air Force Base and Enon, and I-675, a bypass route of Downtown Dayton.

After another interchange with US 68, I-70 passes south of Springfield and serves three exits, the easternmost of which serves as one of the many junctions I-70 has with the National Road (today known as US 40).

Central Ohio

I-70 is a major freeway within the Columbus metropolitan area, serving as the primary east–west route. 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. Between the I-270 interchanges on I-70, hazmats are prohibited. I-70 continues toward Downtown Columbus and, upon entering Valleyview, reaches I-670, a highway serving north-central Columbus as well as both Easton Town Center and John Glenn Columbus International Airport. I-70 itself continues south and meets up with I-71 and SH 315 in a major interchange to the east of Franklinton. For just over 1.5 miles (2.4 km), I-71 and I-70 run concurrently in south Downtown Columbus before I-70 separates and continues west for about nine miles (14 km) before reaching I-270's eastern interchange with I-70, but not before serving three exits in the Bexley area and an interchange with US 33. Throughout the rest of the route in central Ohio, I-70 serves state routes and rural towns like Kirkersville and Buckeye Lake.

I-70 is also the only major expressway within the Zanesville area and bisects the central business district and serves the area with exits to both the central business district and Zanesville Municipal Airport. 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.

Eastern Ohio

Running roughly parallel with both US 22 and US 40, I-70 passes through Georgetown to serve Cambridge, which is also where I-70 interchanges with I-77. Between the I-77 interchange and St. Clairsville, I-70 is a rural highway with few exits serving small towns along its path.

In St. Clairsville, I-70 connects with the Ohio Valley Mall and is less than 10 miles (16 km) from Wheeling, West Virginia. Eastbound traffic can either continue on I-70 toward Wheeling's central business district or use I-470 as a bypass of Wheeling. I-70 itself serves a few more exits in Wheeling's western area before crossing the Fort Henry Bridge and the state line into downtown Wheeling.

Interstate 70 Alternate

Interstate 70 Alternate (I-70 Alt.) is an alternate route for I-70, bypassing several exits on I-70. It is 22 miles (35 km) in length, following the Dayton International Airport Connector, US 40, and US 68.^{[citation needed]}