By 1946, PA 501 was extended north from Myerstown to US 22 (which had replaced PA 43) in Bethel, replacing the entire length of PA 243. The remainder of the road between Bethel and Pine Grove was paved by 1950. By 1953, the route was extended north to a new alignment of US 22 (which also now carries I-78) north of Bethel. By 1960, the southern terminus of PA 501 was cut back to its current location, eliminating a concurrency with US 222. PA 501 was extended north to PA 895 near Pine Grove by 1966.