The east end was moved to its current location at US 15 in the 1950s, with a realigned US 15 replacing the section of PA 641 north on 32nd Street to Carlisle Pike.

The route continues through woodland with sparse homes and curves to the east, running through a mix of fields and trees and passing through the community of Neelyton.

The road heads into farmland with some woods and homes, coming to an intersection with PA 75 in the community of Spring Run.

PA 641 continues through farmland with some woods before it curves east into forested areas, where it heads northeast to ascend Kittatinny Mountain.

The route curves northeast and then south to intersect the eastern terminus of PA 641 Truck at the base of the mountain.

Past the mountain, the road heads east into the community of Roxbury, where it passes homes and a few businesses and comes to an intersection with PA 997.

PA 641 continues east and leaves Roxbury, where it becomes Newburg Road and heads east-northeast through farmland with some trees and residences, passing through the community of Otterbein.

[2][4] After crossing Laughlin Run, this route enters Hopewell Township in Cumberland County and continues through agricultural areas with a few homes.

The route reaches the community of Green Spring and turns northeast, running through more rural areas with some development.

[2][5] PA 641 continues northeast through farmland with some woods and homes, passing through Bears Crossroads and West Hill, where the name changes to Newville Road.

Here, PA 641 turns south onto North Orange Street and passes under Norfolk Southern's Shippensburg Secondary railroad line before it comes to an intersection with US 11.

[2][5] At this point, PA 641 turns east for a concurrency with US 11 on West High Street, passing between the railroad tracks to the north and businesses to the south.

US 11/PA 641 runs through more of the college campus and comes to an intersection with PA 74, at which point that route joins US 11/PA 641 on West High Street.

The three routes head into the commercial downtown of Carlisle, where it comes to an intersection with PA 34 at Hanover Street at the center of town.

The road comes to a bridge over the Pennsylvania Turnpike (I-76) and heads into residential areas, passing through the community of Trindle Spring.

PA 641 enters the borough of Mechanicsburg and becomes West Main Street, passing a mix of homes and businesses.

The route heads into business areas and leaves Mechanicsburg for Hampden Township, where it becomes East Trindle Road and crosses Norfolk Southern's Shippensburg Secondary at-grade.

The road continues northeast past homes and commercial establishments a short distance to the south of Naval Support Activity Mechanicsburg.

[2][5] PA 641 passes under a Norfolk Southern branch line serving the naval facility and continues through developed areas.

PA 641 Truck curves to the east and runs through farmland before it turns southeast onto Cold Spring Road, still following SR 4006.