US 222 enters the borough of Quarryville and becomes South Church Street, heading north past homes. The route comes to an intersection with PA 372, at which point it turns west-southwest to join that route on West State Street, running through more residential areas. US 222 splits from PA 372 by heading northwest onto West 4th Street, passing between businesses to the southwest and homes to the northeast before running through more residential areas, cutting through a corner of East Drumore Township before heading into Providence Township. At this point, the route enters the Pennsylvania Dutch Country of eastern Lancaster County, which is home to many Amish farms. 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. The road crosses the Big Beaver Creek into Strasburg Township and heads northwest through more rural land with some development, with the creek parallel to the southwest. The creek bends away to the west and US 222 continues into agricultural areas with occasional homes, passing through the community of Martinsville and turning to the west-northwest. The route passes to the northeast of the community of Refton and curves northwest, crossing the Pequea Creek into West Lampeter Township. The road heads north through farmland and bends northwest to reach an intersection with PA 741. Here, PA 741 becomes concurrent with US 222 and the two routes curve to the west-southwest, passing between farm fields to the north and residential and commercial development to the south and heading into the community of Willow Street. Here, the road comes to an intersection with PA 272, which is split into a one-way pair at this point.