US 222 bypasses Trexlertown on a multilane divided expressway before coming to its northern terminus at I-78/PA 309 in Dorneyville, where the road continues into Allentown as PA 222.

From this intersection, the route heads northwest on two-lane undivided Rock Springs Road, passing through a mix of fields and woods with some homes.

The route runs through farmland with some woods and homes, curving northeast before heading back to the north and passing to the east of the Robert Fulton Birthplace.

The road heads north and enters East Drumore Township, continuing through farmland with some trees and residences and passing through the communities of Unicorn and Mechanics Grove.

[5][6] In Providence Township, the route becomes Beaver Valley Pike and passes under the Enola Low Grade Trail before it runs through a mix of farmland, woodland, and residential and commercial development.

Both directions of Willow Street Pike rejoin and it continues north as a two-lane undivided road past commercial development before it runs through wooded residential areas, passing through Hollinger.

The southbound direction intersects PA 324 in Engleside before the two routes continue into the city of Lancaster, heading into urban residential and commercial areas.

The two routes continue northeast as a three-lane road with a center left-turn lane and runs past businesses and a few homes before it comes to an interchange with the US 30 freeway.

The route passes near businesses at the interchange before it turns northeast and runs through wooded areas with some nearby residential development and farm fields.

Here, the freeway crosses into Cumru Township and runs north-northeast through more rural areas, coming to a diamond interchange that connects to Grings Hill Road west of the borough of Mohnton.

[3][7] A short distance later, US 222 comes to a northbound exit and southbound entrance with the southern terminus of US 222 Bus., a business route that passes through the city of Reading, which US 222 bypasses to the west.

From here, the route curves to the north and crosses back into Spring Township, passing near suburban residential development and coming to a partial cloverleaf interchange with PA 724 in a business area.

The route crosses into Wyomissing and comes to an interchange with US 422 and the western terminus of US 422 Bus., at which point it also passes over Norfolk Southern's Harrisburg Line.

At this interchange, US 422 becomes concurrent with US 222, and the two routes continue east-northeast along the six-lane Warren Street Bypass freeway, running between residential areas to the northwest and the Norfolk Southern tracks to the southeast.

Following this, US 222/US 422 passes between the Berkshire Mall to the west and commercial areas to the east before it reaches an interchange with Paper Mill Road and Crossing Drive, where it curves to the northeast and runs near more businesses.

[3][7] The route between US 422 and the northern end of this expressway portion is known as the Outer Bypass, the POW/MIA Memorial Highway by an act of the Pennsylvania General Assembly, or the "Road to Nowhere" as it was known while incomplete and to this day.

[8] The route runs between a shopping center to the southwest and Tulpehocken Valley County Park to the northeast prior to reaching the Spring Ridge Drive exit.

At this point, the freeway turns north and crosses the Tulpehocken Creek into Bern Township and runs north-northeast through wooded areas with some nearby homes and commercial development, coming to a partial cloverleaf interchange with PA 183.

Following this, US 222 curves northeast, passing to the northwest of Reading Regional Airport and running through farm fields before crossing the Schuylkill River into Muhlenberg Township.

The route enters Maidencreek Township and becomes a five-lane road with a center left-turn lane, running through a mix of fields and woods with some homes.

[3][7][9] US 222 continues northeast through farmland with some trees, residences, and businesses, passing through Kirbyville and crossing into Richmond Township, where the name becomes Kutztown Road.

US 222 crosses back into Maxatawny Township and curves east, passing over the Sacony Creek and coming to a partial cloverleaf interchange with the southern terminus of PA 737 that provides access to Kutztown.

From here, US 222 becomes two-lane undivided Kutztown Road and runs east-northeast through farmland before heading past businesses near the Long Lane intersection.

Here, US 222 widens to six lanes and becomes Hamilton Boulevard again, heading east-northeast to the north of a park and ride lot before it comes to its northern terminus at a partial cloverleaf interchange with I-78/PA 309 in Dorneyville.

[69] The Maryland State Highway Administration proposed and AASHTO approved the redesignation of US 222 to MD 222 from US 40 in Perryville to US 1 in Conowingo in February 1996; however, this had already been enacted officially and marked publicly in 1995.

[citation needed] On January 29, 2005, the service road at the PA 272 and the Pennsylvania Turnpike interchange was officially named Colonel Howard Boulevard.

On July 5, 2012, a portion of the southbound roadbed near the Berks County line had to close due to an 8-inch buckle in the road surface caused by the hot weather.

[83] In 2010, officials in Berks County pushed for PennDOT to widen a portion of the two-lane road to four lanes due to traffic and safety issues.

[91] In 2021, preliminary design began on a project to widen US 222 between Maidencreek Township and the southern end of the Kutztown Bypass to a four-lane road with a median barrier preventing left turns and cross traffic.

Preliminary engineering to widen US 222 between the northern end of the Kutztown Bypass and the Lehigh County line is not expected to take place until the late 2020s.