Through Geauga and Ashtabula Counties, US 322 is named Mayfield Road until it enters Pennsylvania. In Geauga County, US 322 passes through suburban Chesterland and into Ohio's second largest Amish community, which includes the rural townships of Claridon and Huntsburg. In Ashtabula County, US 322 crosses through Windsor Township, the village of Orwell, and Williamsfield Township before crossing the Ohio-Pennsylvania state line south of Pymatuning Reservoir.
In the State College area, the current alignment of US 322 overlaps US 220 for 6 miles. The highway is expected to be concurrent with Interstate 99 along with US 220 from Port Matilda to I-80 near Mount Eagle; the concurrency will take place when the I-99 extension is completed. Northeast of Port Matilda, US 220 and US 322 depart the Appalachian Thruway via an interchange and proceed east on the 28th Division Highway while the Thruway continues to the northeast as US 220 Alternate.
East of the overlap, US 322 continues southeastward through State College and its immediate suburbs on the Mount Nittany Expressway. After three exits, US 322 reverts to an at-grade highway two miles east of State College in Boalsburg, merging with US 322 Business and proceeding eastward along Boal Avenue as the route exits the State College area. Between Boalsburg and Lewistown, the highway traverses Tussey Mountain and Jacks Mountain, in the Rothrock State Forest, as it turns to the south.
Between Milroy and Lewistown, US 322 is a limited-access road. After three exits, it briefly overlaps U.S. Route 522 and begins a long overlap with U.S. Routes 22. South of Lewistown, US 22/US 322 enters the Lewistown Narrows, an 8-mile stretch of road through the Juniata River water gap in Shade Mountain. Construction to convert this section of the highway from a two-lane highway to a divided, limited-access four lane highway was completed in December 2007, and it includes building the longest mechanically stabilized earth wall in the U.S. The highway exists the narrows in Arch Rock, traverses Juniata County and Perry County, and crosses the Tuscarora Mountain through a water gap on a southeasternly course along the banks of the Juniata River. South of the Susquehanna crossing, the freeway is parallel to the river for 15 miles before entering the Harrisburg Area.
North of downtown Harrisburg, the US 22/322 overlap interchanges with Interstate 81 at exit 67. While US 22 continues through the interchange and heads into downtown, US 322 departs US 22 and joins I-81 northbound. I-81 and US 322 remain concurrent for three miles to exit 70, where US 322 exits, following Interstate 83, which has its northern terminus at the interchange, south through the innermost suburbs of Harrisburg. After two exits, US 322 returns to an at-grade roadway at the Eisenhower Interchange (exit 47), departing I-83 and following Paxton Street east toward Hummelstown. West of the borough, US 322 becomes a freeway once again, becoming the Hummelstown Bypass after crossing Fiddlers Elbow Road. The route runs south of Hummelstown, interchanging with two local roads before meeting the eastern terminus of Pennsylvania Route 39 and the western terminus of U.S. Route 422 at an interchange midway between Hummelstown and Hershey.
US 322 heads east from the interchange, becoming the at-grade West Governor Road as it passes south of Hershey. East of the Hershey Area, the route runs eastward via the scenic Horseshoe Pike. The Horseshoe Pike portion ends west of Cornwall, where US 322 bypasses the town. East of the bypass, the route becomes grade-leveled again, passes under the Pennsylvania Turnpike (I-76), and runs eastward known as the 28th Division Highway. East of Ephrata, US 322 interchanges U.S. Route 222. Between US 222 and Downingtown, the route runs southeastward through the Pennsylvania Dutch Country. In Downingtown, US 322 interchanges U.S. Route 30.
Where the highway approaches the West Chester Area, it bypasses the borough via West Chester Bypass. At the end of the at-grade bypass, the eastbound lane of US 322 merges onto U.S. Route 202 southbound to begin an overlap. After three exits, the US 202/US 322 overlap becomes grade leveled running north-south. South of West Chester, the overlap is a major divided highway in Delaware County. In Concord Township, US 322 turns east onto U.S. Route 1 and leaves U.S. Route 202 at Painters' Crossroad. One mile conjoined with US 1 east of US 202, US 322 leaves US 1 via a turn southeastward to become the Conchester Highway. Approaching Chester, the route has three exits (one with PA 452, Bethel Road at the CSX rail line, and Highland Avenue) before beginning an overlap with Interstate 95, at exit 3A. The overlap with I-95 is a brief one, where US 322 leaves I-95, at exit 4, and crosses the Delaware River to enter New Jersey via the Commodore Barry Bridge.