In Pennsylvania, I-78 runs for about 78 miles (126 km) from the western terminus at I-81 in Union Township east to the New Jersey state line near Easton in Northampton County.

Following this, the freeway passes through more rural areas with some nearby development and reaches a westbound exit and eastbound entrance with US 22 (William Penn Highway).

[3][4] I-78/US 22 enters Bethel Township in Berks County and heads east-northeast through agricultural areas to the south of the Blue Mountain ridge, coming to a diamond interchange with PA 645 north of Frystown.

Past this interchange, the road runs through a mix of farms and woods, crossing the Little Swatara Creek into Upper Tulpehocken Township.

I-78/US 22 crosses Northkill Creek into Upper Bern Township and comes to a diamond interchange with Mountain Road north of Shartlesville.

[3][5] In Tilden Township, the freeway continues northeast and reaches a partial cloverleaf interchange with PA 61 in a business area that includes a 250,000-square-foot (23,000 m2) Cabela's store.

The road continues east through rural land with some nearby development, passing through the northern corner of Maxatawny Township.

Following this interchange, the freeway heads to the south of more warehouses and runs through more rural areas with some homes, crossing into Upper Macungie Township.

I-78/US 22 runs between farm fields to the north and warehouses and industrial development to the south before it comes to a cloverleaf interchange with PA 100 in a business area in Fogelsville.

After the PA 100 interchange, the freeway widens to six lanes and heads east through industrial areas, coming to a bridge over Norfolk Southern Railway's C&F Secondary railroad line before curving northeast.

In Kuhnsville, US 22 splits from I-78 at an eastbound exit and westbound entrance by heading northeast on a freeway called the Lehigh Valley Thruway.

Past the hospital, I-78/PA 309 comes to a partial cloverleaf interchange with the northern terminus of the southern section of PA 29 at Cedar Crest Boulevard before running between residential areas to the north and office buildings to the south.

The freeway enters Allentown and runs through woodland, crossing Little Lehigh Creek before it passes through a small section of Salisbury Township.

I-78/PA 309 runs near industrial areas and passes over Norfolk Southern Railway's Reading Line before coming to a westbound exit ramp serving Emaus Avenue.

The highway comes to an eastbound exit and westbound entrance with Rock Road that provides a connection to PA 145 in Summit Lawn, where it crosses into Upper Saucon Township.

The road comes to a trumpet interchange with the southern terminus of the PA 33 freeway, which heads north toward the Pocono Mountains region.

[16] In 2020, a project began to improve the section of I-78 in Hamburg by reconstructing and reconfiguring the PA 61 interchange and widening and rehabilitating the bridges over the Schuylkill River and Port Clinton Avenue.