The highway runs approximately 435.66 miles (701.13 km) from an interchange with I-71 west of Akron, Ohio, east to I-295 in Bellmawr, New Jersey.

At Valley Forge, I-76 becomes the Schuylkill Expressway, eventually enters Philadelphia, and then crosses the Walt Whitman Bridge into New Jersey.

After only about three miles (4.8 km) in New Jersey, I-76 reaches its eastern terminus, though the freeway continues south as Route 42.

I-76 begins at exit 209 of I-71 in Westfield Township, approximately six miles (9.7 km) east of Lodi, Ohio; U.S. Route 224 (US 224) continues west from the end of I-76.

I-76 then passes through Wadsworth, Norton, and Barberton and then enters Akron; this section of road was built as US 224.

Shortly after heading north from the I-277 interchange, I-76 meets I-77 and again turns east, joining southbound I-77 south of downtown Akron on the West Expressway.

West of Youngstown, the freeway intersects the Ohio Turnpike and I-80 via a double trumpet interchange.

After the Grays Ferry Avenue exit near University City, I-76 crosses the Schuylkill Expressway Bridge to go toward the South Philadelphia Sports Complex near Lincoln Financial Field, Wells Fargo Center, and Citizens Bank Park.

While the South Jersey Transportation Authority (which owns the A.C. Expressway) is not against the idea of making the freeway section of Route 42 and the A.C. Expressway an eastern extension of I-76, they feel that making the change without a compelling reason would only add to motorists' confusion in southern New Jersey.

(Some early plans called for a new freeway along SR 14 to the Pennsylvania state line; it is unclear when the proposed route was shifted to the turnpikes.)

I-78 was assigned to a route from Norwalk, paralleling SR 18 through Akron to Youngstown and turning south there to end at the planned I-80.

The 1957 numbering, however, was drawn on a map from 1947, which did not include several changes that had been approved, specifically the Keystone Shortway across Pennsylvania.

The former alignment through Cleveland became I-80N; the turnpike was still not assigned a number from near Elyria (where I-80N and I-90 would split from it) to west of Youngstown.

On April 16, 1963, due in part to the extension of I-79 south from Greater Pittsburgh, Pennsylvania proposed a partial renumbering.

A realignment and extension of I-76 into Ohio, taking over the rest of I-80S to I-71 east of Lodi, was approved January 11, 1972.

U.S. Department of Transportation research into federal documentation of the I-76 renumbering found no evidence of this being intentional.