PA 645 heads north from Myerstown into agricultural areas and enters Berks County, where it passes through Frystown and comes to an interchange with Interstate 78 (I-78)/US 22.

Past here, the route heads across forested Blue Mountain and continues into Schuylkill County, where it reaches its northern terminus.

PA 645 runs through agricultural areas with some homes, curving northwest briefly before turning north again onto Kutztown Road.

[3][4] The route enters Tulpehocken Township in Berks County and becomes Camp Swatara Road, running north-northwest through agricultural areas with some homes and commercial development.

[3][5] At the summit of Blue Mountain, PA 645 crosses the Appalachian Trail and heads into Pine Grove Township in Schuylkill County.

At the bottom of the mountain, the route heads through a mix of farmland and woodland with some homes, passing through the community of Brookside.