Upon crossing the Mason–Dixon line, US 222 enters Fulton Township in Lancaster County, Pennsylvania and heads north as Robert Fulton Highway, passing between woodland to the west and farm fields to the east. The route turns to the north-northwest and runs through agricultural areas with some trees and homes, passing through the community of New Texas Lyles. The road continues through rural areas and curves to the north, heading into the residential community of Wakefield and coming to an intersection with PA 272. At this point, PA 272 turns north for a concurrency with US 222 along Robert Fulton Highway, running through a mix of farms and homes. PA 272 splits from US 222 in the community of Penn Hill by heading northwest, and US 222 continues northeast through wooded areas. The road heads into a mix of fields and woods and reaches the community of Goshen, where it turns to the north. 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. US 222 continues north-northeast through rural land and passes through the community of Bethel, where it crosses into Little Britain Township. 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. The route passes east of Solanco High School and bends to the north-northwest as it runs through more rural land.