The William Penn Highway was an auto trail that ran from Pittsburgh, Pennsylvania in the west to New York City in the east.

From here to Armagh, the highway closely follows modern-day US 22, though this route bypasses town centers historically served by the William Penn.

At Armagh, a loop following the north bank of the Conemaugh River serviced Johnstown, and has since been replaced by PA 403 and William Penn Avenue, connecting back to the main highway at Mundy's Corner.

From here, the highway paralleled the Pennsylvania Railroad closely, turning north on US 220 Business and Old US 220 to Tyrone, then south to Water Street, where it meets today's course of US 22 again.

After a brief stretch of modern US 322, the road passed through Hummelstown on Main Street, then crossed over the Reading again to follow Chocolate Avenue through Hershey.