The route runs through rural areas with some development, curving northeast and then east again before coming to a partial cloverleaf interchange with PA 18 near The Pavilion at Star Lake.

The four-lane freeway heads east-southeast between Downtown Pittsburgh to the north and the Monongahela River to the south, reaching a partial interchange with Stanwix Street with no eastbound exit.

In Wilkinsburg, the freeway comes to an interchange with the southern terminus of PA 8, where US 30 splits from I-376/US 22 on the Penn-Lincoln Parkway by heading southeast at-grade on Ardmore Boulevard.

[4][5] Past this interchange, I-376/US 22 continue northeast through suburban development, crossing into the borough of Churchill and reaching an eastbound exit and westbound entrance with Greensburg Pike.

The route continues past a mix of rural areas and development, passing to the south of the borough of Export and crosses Turtle Creek again before leaving Murrysville.

Past this interchange, the road runs east-northeast through rural areas with occasional development, turning east and coming to an intersection with PA 819 in Five Points.

At the PA 403 interchange, the freeway section ends and US 22 continues east-southeast as a four-lane divided highway with at-grade intersections through rural land with some development.

The freeway continues southeast and passes over Norfolk Southern Railway's Pittsburgh Line prior to coming to a partial cloverleaf interchange with PA 53 south of the borough of Cresson.

US 22 turns northeast and runs between developed areas to the northwest and a railroad yard to the southeast before it crosses a Norfolk Southern Railway spur at-grade and curves east, leaving Hollidaysburg.

[4][5] East of Hollidaysburg, US 22 becomes an unnamed two-lane undivided road and heads into rural areas with some development, curving northeast and passing through Frankstown, where it briefly gains a center left-turn lane.

US 22 curves east as a three-lane road with a center left-turn lane and runs a short distance to the north of the Frankstown Branch Juniata River, passing through a gap in Tussey Mountain.

The road turns to the southeast and crosses the river near Alfarata, continuing though rural land with some development and coming to an intersection with the western terminus of PA 305 south of the borough of Alexandria.

Farther southeast, the road heads into commercial areas and turns into a four-lane divided highway as it comes to a partial cloverleaf interchange with PA 26.

The road curves east and passes over the Juniata River and Norfolk Southern Railway's Pittsburgh Line before coming to an interchange with Penn Street that provides access to Huntingdon and PA 26.

[4][5] US 22 enters Mifflin County and becomes an unnamed three-lane road with a center left-turn lane, passing through Lucy Furnace and coming to an intersection with the northern terminus of PA 747.

Following this, the route becomes a four-lane road and turns into a divided highway before it reaches a junction with US 522 north of the borough of Mount Union on the opposite side of the Juniata River.

Here, the road gains a center left-turn lane and heads through developed areas, curving to the north and running a short distance to the west of the Juniata River.

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.

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 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 Railway's Buffalo Line, curving to the east.

At this point, the freeway enters 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.

The freeway ends and the route becomes North Cameron Street, a four-lane divided highway with at-grade intersections that heads to the east of the Pennsylvania Farm Show Complex & Expo Center.

US 22 turns southeast onto four-lane divided Arsenal Boulevard, with PA 230 continuing south (east) along North Cameron Street toward Downtown Harrisburg.

[4][5] I-78/US 22 enters Berks County and heads east-northeast through rural areas to the south of the Blue Mountain ridge, coming to a diamond interchange with PA 645 north of Frystown.

After the PA 100 interchange, the freeway widens to six lanes and heads east through industrial areas, coming to a bridge over Norfolk Southern Railway's C&F Secondary railroad line before curving northeast.

The freeway heads through developed areas and reaches a partial cloverleaf interchange with PA 248, where it turns northeast and runs along the northern border of the borough of Wilson.

In their own times, these companies constructed a highway across the Appalachian Mountains collectively called the Northern Pike, but all folded with competition from the Main Line of Public Works and, later, the Pennsylvania Railroad.