When routes were first legislated in Pennsylvania in 1911, the current route of PA 501 was not given a route number. PA 501 was designated in 1928 to run from PA 72 (Prince Street) in Lancaster north to PA 5 (now US 322) in Brickerville, running along a paved road. The route headed east from PA 72 on Liberty Street before it turned north and followed Lititz Avenue out of Lancaster, continuing along its current alignment to Brickerville. PA 243 was designated in 1928 to run from US 22/PA 3 (now US 422) in Myerstown north to PA 43 (now Old Route 22) in Bethel, following an unpaved road. PA 243 was paved by 1930. The road between Brickerville and Myerstown and Bethel and Pine Grove was an unnumbered, unpaved road. In the 1930s, PA 501 was extended north from US 322 in Brickerville to US 422 and the southern terminus of PA 243 in Myerstown along a paved road. Also, US 222 was designated concurrent with the route between PA 72 at Prince Street and Oregon Pike. By this time, the unnumbered road between Bethel and Pine Grove was paved except for a portion crossing Blue Mountain.