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.

Along the turnpike, the route runs approximately 326 miles (525 km) across most of the southern portion of the state, serving the Pittsburgh and Harrisburg areas.

After entering Philadelphia, I-76 crosses the Delaware River on the Walt Whitman Bridge into New Jersey.

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.

The new expressway largely followed the earlier planned parkway route from Valley Forge to Fairmount Park, while also extending into southern Philadelphia and across the Delaware River into New Jersey.

Two alternatives were proposed south of University City: one routing would continue along the west bank of the river into Southwest Philadelphia to its confluence near Philadelphia International Airport, where it would tunnel underneath the Delaware to Paulsboro, New Jersey; the other would cross the Schuylkill south of University City and bisect South Philadelphia, crossing the Delaware River into Gloucester City, New Jersey.

Planned expansions of the airport in the path of the former proposal led to adoption of the routing through South Philadelphia.

[13] Immediately after its completion, operational studies performed on the Schuylkill Expressway found that the route would be unable to cope with the area's growing traffic demands, due to the many substandard design elements and compromises incorporated to cope with the rugged, difficult routing of the road.

[14] PennDOT completed a scaled back version of a $23.7-million (equivalent to $32.9 million in 2023) project to add 29 webcams on the Schuylkill Expressway between the Conshohocken Curve and Passyunk Avenue.

[15] On the afternoon of June 8, 2011, a section of the Schuylkill Expressway near Grays Ferry Avenue buckled from temperatures around 100 °F (38 °C), causing lane closures.

For hours, motorists were stuck at various locations in both directions between I-476 and Girard Avenue until the mess could be cleaned up.

The project incorporates variable-message signs to alert motorists to traffic congestion ahead.

It could also coordinate with SEPTA to provide motorists with real-time mass transit information to give commuters an option to exit the highway and use public transportation to finish their trip at some point.