Past this interchange, the three routes reach an intersection with the southern terminus of PA 102 before curving north and entering Meadville upon crossing French Creek and a Western New York and Pennsylvania Railroad line.

US 322 reaches an intersection with the southern terminus of PA 417, at which point it turns south onto four-lane undivided 13th Street, crossing the Western New York and Pennsylvania Railroad line at-grade.

US 322 curves south and enters the borough of Clarion, where it narrows to two lanes and becomes North 1st Avenue, running through developed areas and passing east of Memorial Stadium.

Upon leaving Corsica, the route turns into an unnamed road and runs a short distance to the south of I-80, passing through the community of Roseville and curving to the east-southeast.

On the eastern border of Brookville, PA 28 splits to the east and US 322 continues southeast through rural areas as an unnamed road, crossing Mill Creek in the community of Port Barnett.

US 322 continues southeast and comes to an intersection with the southern terminus of PA 950 before it crosses a Buffalo and Pittsburgh Railroad line at-grade and Sandy Lick Creek.

Farther east, US 322 reaches an intersection with PA 153, where it turns southeast to form a concurrency with that route on four-lane divided Rockton Mountain Highway.

The two routes enter more developed areas north of the borough of Clearfield as a three-lane road with a center left-turn lane, crossing a R.J. Corman Railroad line at-grade.

US 322 narrows back to two lanes and passes through the community of Mineral Springs before it comes to an intersection with the southern terminus of PA 970, where the name changes to Woodland Bigler Highway.

Upon reaching the northern border of the borough of Philipsburg, US 322 splits from PA 53 by turning northeast onto Railroad Street, a three-lane road with a center left-turn lane.

US 322 becomes Port Matilda Highway and passes a westbound runaway truck ramp as it runs through rural areas, ascending Black Bear Hill.

Following this, the median narrows and the four-lane divided highway enters the Bald Eagle Valley, coming to an eastbound exit and westbound entrance with North High Street that provides access to the borough of Port Matilda.

The road turns south and then southwest before it reaches an eastbound runaway truck ramp and makes a curve to the southeast, passing west of the Laurel Creek Reservoir.

The route turns south through forests and enters the agricultural Kishacoquillas Valley, where it comes to a trumpet interchange connecting to Old US Hwy 322 that provides access to the community of Milroy.

Past this interchange, US 22/US 322 curves south along the eastern border of Lewistown and crosses a Juniata Valley Railroad line at-grade before reaching an eastbound exit and westbound entrance with East Charles Street.

The two routes curve east and come to a westbound exit and eastbound entrance with the eastern terminus of US 22 Bus., at which point the freeway begins to parallel the Juniata River located south of the road.

Farther east, the freeway curves to the southeast and exits the Lewistown Narrows, heading further from the river and coming to a diamond interchange with Arch Rock Road.

The two routes head northeast and then southeast, crossing Lost Creek before turning south and reaching a diamond interchange with PA 35 east of the borough of Mifflintown.

The freeway curves south as it passes west of Buffalo Mountain, making a turn east away from the river and reaching a diamond interchange with PA 34 northeast of the borough of Newport.

US 22/US 322 reaches a westbound exit and eastbound entrance with Meadow Grove Road that provides access to the community of Midway and curves southeast alongside the river.

Past this interchange, US 22/US 322 heads east-southeast through rural areas to the north of the Susquehanna River and Norfolk Southern's Buffalo Line, curving to the east.

Past the mountain, the freeway runs near developed areas farther from the river and comes to a partial cloverleaf interchange with PA 443 in the community of Fort Hunter.

At this point, the freeway enters the city of Harrisburg and runs between Wildwood Park to the west and developed areas to the east, curving south and crossing Paxton Creek before coming to a stack interchange with I-81.

After crossing South Mountain, the road passes over the Pennsylvania Turnpike (I-76) and runs through a mix of rural areas and development, intersecting PA 501 in the community of Brickerville.

[3][4] Following the US 222 interchange, the road becomes two-lane undivided Division Highway continues southeastward through the Pennsylvania Dutch Country of eastern Lancaster County, which is home to many Amish farms.

Past this interchange, US 322 passes north of a park and ride lot and becomes Manor Avenue, a three-lane road with a center left-turn lane that enters the borough of Downingtown.

Here, the route passes through developed areas, heading to the south of Downingtown West High School, and narrows to two lanes before coming to an intersection with US 30 Bus.

At this point, US 322 heads onto the Commodore Barry Bridge, passing over Conrail Shared Assets Operations' Chester Industrial Track line and running to the northeast of Subaru Park, the home stadium of the Philadelphia Union of Major League Soccer, before it crosses the Delaware River into New Jersey.

[15] To decrease congestion and improve safety, the Pennsylvania Department of Transportation (PennDOT) began a project in 2014 to reconstruct US 322 from the Centre/Mifflin county line to the route's interchange with PA 144, at a cost of about $93 million.

[22] Construction on the project to widen the Conchester Highway section of US 322 began on April 28, 2017, with Governor Tom Wolf, PennDOT secretary Leslie Richards, and other state and local officials in attendance for a groundbreaking ceremony.