After that, it climbs into the Pocono Mountains to run through the Wyoming Valley, then exits into New York.

About a mile (1.6 km) north of Carlisle at exit 52, it meets US 11, which connects to the Pennsylvania Turnpike/I-76 (halfway between Philadelphia and Pittsburgh), since I-81 has no direct interchange with I-76.

[3][4] The stretch of US 11 connecting I-81 to I-76 is known locally as the "Miracle Mile" since it contains plenty of traveler services including restaurants, gas stations, lodging, truck stops, and shops.

North of Harrisburg between I-83/US 322 and I-78, the highway passes near Hershey and Fort Indiantown Gap.

[3][4] At milemarker 89, I-81 meets the western terminus of I-78; I-78 picks up the eastward route through the Great Valley and heads toward Allentown and New York City, while I-81 turns back northward, cutting through Blue Mountain at Swatara Gap.

The section from Scranton to the New York state line was planned as a continuation of the Northeast Extension of the Pennsylvania Turnpike.

The fire resulted in about 10 miles (16 km) of I-81 being closed in both directions, with traffic being diverted along the southern portion of the Capital Beltway.

The turnpike between the two I-81 interchanges carries an average of 10,000 vehicles per day versus 80,000[10] on the parallel segment of I-81.

[12] On October 24, 2018, the Pennsylvania Department of Transportation (PennDOT) released their plans for a new exit 12 on I-81, at Guilford Springs Road, estimated to cost around $23 million.

[13] The purpose for the exit is to improve access for trucks to the various distribution warehouses south of Chambersburg, such as Target.