I-80 serves many smaller cities in central to northern Pennsylvania, including Sharon, Clarion, DuBois, Bellefonte, Lock Haven, Milton, Bloomsburg, Hazleton, and Stroudsburg.

From the state of Ohio, I-80 enters the Western Pennsylvania area which encompasses Mercer, Venango, Butler, Clarion, Jefferson, and Clearfield counties.

I-80 then ascends Sugar Valley Mountain and then follows White Deer Creek down to the West Branch Susquehanna River, which I-80 crosses a second time.

I-80 enters Northeastern Pennsylvania and proceeds from Northumberland County in the west to the Pennsylvania-New Jersey border in the east.

I-80 intersects I-476, the Pennsylvania Turnpike Northeast Extension, at exit 277 in Carbon County for connections to Allentown and Philadelphia to the south.

Between exits 293 and 298, there is a rest area on the eastbound side with public restrooms and picnic tables but no food or gas.

Shortly after at exit 310 (the easternmost interchange in Pennsylvania), PA 611 intersects I-80 for the last time before starting its southerly route down the Delaware River, gradually moving away from I-80.

[citation needed] In early plans for the Interstate Highway System, the connection across Northern Pennsylvania would have paralleled US 6N and US 6 from what became I-90 near West Springfield east to Scranton.

On May 22, 1957, a request by Pennsylvania to move the corridor south was approved by the Federal Highway Administration (FHWA).

However, when the initial numbers were assigned later that year, they were drawn on a 1947 map, and so the corridor across Northern Pennsylvania became part of I-84, while the Scranton–New York route became I-82.

[5][6] On March 7, 2011, the supporting wall on the eastbound I-80 bridge over Sullivan Trail in Tannersville collapsed from snow and rain.

[8] On December 18, 2020, a snow squall caused an accident on this highway that generated a massive pileup of 66 vehicles (mainly trucks).

Representatives John E. Peterson and Phil English proposed a federal transportation bill that would ban the tolling of I-80.

The chief executive officer of the PTC promised that the tolls would be used on highway projects in Pennsylvania and not on mass transit.

[10][16] On September 11, 2008, the FHWA rejected Pennsylvania's application to toll I-80 a second time, stating: "There is simply no evidence that the lease payments [by the Turnpike Authority] are related to the actual costs of acquiring an interest in the facility.

"[17] On April 6, 2010, the FHWA rejected the application for the third time, with the statement: "We based today's decision on what is allowable under federal law.

The Interstate System Reconstruction and Rehabilitation Pilot Program requires that revenue from tolls be used only to improve the tolled facility, in this case I-80, and not be directed toward other state funding needs or transportation projects elsewhere in the state, as is the case in the Pennsylvania application.

The new interchange will eliminate local access between PA 26 (Jacksonville Road) and I-80, which will be provided by a new exit two miles (3.2 km) to the east.

[19][20] The local access interchange between PA 26 and I-80 was funded in part by a $35-million federal grant, with a total estimated cost of $52 million.

The project had a completion date of 2023, has been approved by PennDOT and the US Department of Transportation (USDOT), and is in the final design phase.

This section of road was built in the 1950s and is one of the oldest stretches of Interstate Highway in the US, starting out as a simple bypass of Stroudsburg for US 209 before becoming part of I-80.

It has one of the highest accident rates in Pennsylvania due to major issues such as most entrances not having acceleration lanes, multiple overpasses that are structurally deficient, and shoulders that are as narrow as a tenth the required length for Interstate Highways.