The portion of the road in northern Lancaster County was originally established as two private turnpikes in the 19th century, becoming a public road in 1926. PA 501 was designated in 1928 to run from PA 72 in Lancaster north to PA 5 (now US 322) in Brickerville while PA 243 was designated onto the road running between US 22/PA 3 (now US 422) in Myerstown and PA 43 in Bethel. PA 501 was extended north to US 422 in Myerstown during the 1930s. By 1946, the route replaced PA 243 and continued north to US 22 in Bethel. PA 501 was extended to a new alignment of US 22 north of Bethel by 1953. The southern terminus was cut back to its current location by 1960 to eliminate a concurrency with US 222. By 1966, PA 501 was extended north to PA 895. In 2013, the route was realigned to bypass the center of Schaefferstown to the west.