I-78 begins at a directional-T interchange with Interstate 81 in Union Township, Lebanon County, Pennsylvania, about 25 miles (40 km) northeast of Harrisburg. Near the east end of the county, at exit 8, U.S. Route 22 merges with I-78.
At exit 51, in Upper Macungie Township, US 22 leaves the freeway. Passengers traveling on I-78 eastbound must use this exit to access I-476 (Northeast Extension of the Pennsylvania Turnpike) and westbound travelers must use exit 53. From exits 53 to 60, I-78 is concurrent with Pennsylvania Route 309. The six lane overlap bypasses the City of Allentown to south and crosses South Mountain.
At exit 60 (A-B going westbound), PA 309 south leaves for the village of Quakertown. Six miles later, Pennsylvania Route 412 interchanges with I-78 in Hellertown. Highway 412 also goes to Bethlehem and Lehigh University. At mile marker 71.04, Pennsylvania Route 33 intersects at Exit 71. Route 33 traverses the Pocono Mountains and goes to Bangor and Interstate 80. The final exit on Interstate 78 in Pennsylvania is for Morgan Hill Road, which goes to Pennsylvania Route 611 and Easton. Interstate 78 then crosses the Interstate 78 Toll Bridge and enters New Jersey.
After the Interstate 78 Toll Bridge, I-78 enters New Jersey as the Phillipsburg-Newark Expressway. The road begins by parallelling County Route 642 in the town of Alpha. At 3.94 miles, Exit 3, a partial cloverleaf interchange brings together U.S. Route 22, New Jersey Route 122 and New Jersey Route 173 with Interstate 78 in Phillipsburg. U.S. Route 22 now becomes concurrent with 78 for the next 15 miles. Going westbound, exit 4 leaves to the right for County Route 637 and Warren Glen. The next exit, Exit 6, is for County Route 632 in Bloomsbury. However the route number is not signed on Interstate 78. Exit 7 is the first of several eastbounde exits for NJ 173. This one is located in Bloomsbury as 173 begins to parallel the interstate. Four miles later, Exit 11 leaves to the right as another Exit for NJ 173. Warren County 614 also is located off the exit. Exit 12, westbound is for NJ 173 again. However, Exit 12 eastbound is for a frontage road parallelling Interstate 78.
Exit 13 is only westbound and is another exit for NJ 173. Nearby the exit, going eastbound, the frontage road merges in. Exit 15 is for NJ 173 and County Route 513 in Franklin Township. Exit 17 is for NJ 31 in Clinton. In the town of Annandale, US 22 leaves Interstate 78 at exit 18. Route 22 continues towards Bound Brook and Union County. At exit 20, Hunterdon CR 639 intersects. Hunterdon 639 heads towards the Round Valley Recreational Area. Exit 24 is for County Route 523 towards Oldwick. At exit 29, Interstate 287, U.S. Route 202 and U.S. Route 206 interchange with 78 in Bedminster. At this point, in Somerset County, Exits 33, 36 and 40 are for county routes in Warren Township. At exit 41, I-78 enters Union County. At exit 45, County Route 527 intersects after parallelling for some time. West of exit 48, I-78 splits into express and local carriageways. Exit 48 is for New Jersey Route 24 in Springfield. Exit 49A is for one of route 24's spur routes, New Jersey Route 124. Going westbound, Exit 52 is for the Garden State Parkway in Irvington. At Exits 57 and 58, New Jersey Route 21, U.S. Route 1, U.S. Route 9 and U.S. Route 22 intersect Interstate 78. The exit provides access to Newark Airport.
East of exit 58 at the eastern tip of Newark, I-78 becomes the Newark Bay Extension of the New Jersey Turnpike. Past the first toll plaza, I-78 interchanges Interstate 95 (New Jersey Turnpike) and crosses the Newark Bay via the Newark Bay Bridge. The first exit, 14A, is for New Jersey Route 440 in Bayonne. Liberty State Park and the Liberty Science Center can be reached by taking Exit 14B. Exit 14C is the final numbered exit, providing access to the New Jersey Turnpike. New Jersey Route 139 becomes concurrent with 78 as it approaches the Holland Tunnel and enters New York.