At this point, the concurrency with southbound US 222 ends and PA 501 continues north as a three-lane road with a center left-turn lane.

The road becomes two lanes again and runs between farm fields to the west and the Lancaster Airport to the east before it crosses into Warwick Township.

[2][3] The route widens into a five-lane road with a center left-turn lane and passes between businesses to the west and farmland to the east.

PA 501 continues into the borough of Lititz and becomes South Broad Street, running past more businesses before becoming lined with homes.

The route continues north and loses the center turn lane before it heads into the commercial downtown and intersects PA 772.

The route leaves Lititz for Warwick Township again and becomes Furnace Hills Pike, running past commercial establishments as a three-lane road with a center left-turn lane.

The road narrows to two lanes and runs near residential neighborhoods before it crosses into Elizabeth Township, heading northeast through a mix of farmland and woodland with some homes.

The route passes through more farmland and woods and comes to a bridge over the Pennsylvania Turnpike (I-76), at which point it heads into forested areas.

[2][3] PA 501 crosses into Heidelberg Township in Lebanon County and becomes Stiegel Pike, continuing north through forests with some farms and homes and passing through the community of Waldeck.

Farther north, the road runs near a few commercial establishments and passes under Norfolk Southern's Harrisburg Line, at which point it enters the borough of Myerstown.

PA 501 heads past industrial buildings before it crosses Tulpehocken Creek and continues north into residential areas.

[2][4] PA 501 enters Tulpehocken Township in Berks County and becomes Lancaster Avenue, heading northeast through farmland with some commercial development before it passes residences and some businesses in the community of Mount Aetna.

PA 501 turns north to remain along Lancaster Avenue, with Rehrersburg Road continuing east, and runs through more rural land.

At this point, the route turns west and remains along Lancaster Avenue, curving to the north into business areas as a three-lane road with a center left-turn lane and reaching an interchange with I-78/US 22.

Past this interchange, PA 501 narrows to two lanes and heads through farmland, turning northwest as it passes to the east of a warehouse.

[2][5] At the summit, the route crosses the Appalachian Trail and enters Pine Grove Township in Schuylkill County, where it becomes Bethel Road and descends the mountain.

The route headed east from PA 72 on Liberty Street before it turned north and followed Lititz Avenue out of Lancaster, continuing along its current alignment to Brickerville.

[26] The realignment was originally expected to be completed in April 2013 but was pushed back due to utility relocation issues.