From I-81, I-88 heads east across the Chenango to Port Dickinson, where it merges with NY 7 (here also a limited-access highway) at exit 1.

Northeast of Oneonta, NY 28 leaves I-88 at exit 17 to follow the Susquehanna River northward toward Cooperstown.

Upon crossing into Schoharie County, I-88 begins to follow an easterly routing as it heads toward Cobleskill.

Howe Caverns, a regionally popular attraction, is located a short distance north of the exit.

I-88 continues onward, skirting the northern edge of Schoharie before passing into Schenectady County.

Past US 20, I-88 continues northeast, interchanging with NY 7 for one final time before ending at the New York State Thruway (I-90) in western Schenectady.

New York state officials pressed for addition of the route, and funding was included in the Federal-Aid Highway Act of 1968.

Right-of-way acquisition started immediately afterward,[4] and I-88 was added to the Interstate Highway System on December 13, 1968.

[2] As originally planned by the New York State Department of Transportation (NYSDOT), I-88 would begin at I-81 in Binghamton and follow the proposed Susquehanna Expressway to Schenectady, from where it would continue to US 4 in Troy over "Alternate Route 7", the limited-access alignment of NY 7 through the northern suburbs of Albany.

[8][14] In 1999 NYSDOT, the Federal Highway Administration (FHWA) and the New York State Thruway Authority (NYSTA) discussed redesignating the Berkshire Connector as I-90 and redesignating the nontoll part of I-90 from Thruway exit 24 to exit B1 on the Berkshire Connector as I-88.

[16] Around 6:20 am, two trucks from different directions drove into the chasm, apparently unaware of it, killing both drivers.

David Swingle, 42, of Waverly, who was driving eastbound, was identified shortly after the accident.

[19] NYSDOT started construction to replace the section of highway almost immediately, and it was reopened August 31.