PA 272 was designated in 1928 to run from US 222/PA 72 in Wakefield east to US 1/PA 12 (Baltimore Pike) in Nottingham, with the road unpaved in Lancaster County and paved in Chester County. Also, the road between the Maryland border and Chrome became the southernmost portion of PA 42. At this time, US 222 replaced the US 230 designation south of Lancaster and PA 240 replaced the PA 41 designation along US 222 between Brownstown and Adamstown. By 1930, PA 272 was paved between PA 172 in Little Britain and the Octoraro Creek. In addition, PA 722 was designated onto the Oregon Pike between Oregon and Brownstown while the concurrent state route designations were removed from US 222. In the 1930s, PA 272 was paved between Wakefield and Little Britain. Also, a southern extension of PA 72 was designated onto the straight road between Wakefield and Willow Street. US 222 was also realigned to use Oregon Pike between Lancaster and Brownstown, replacing the easternmost portion of PA 722. US 222 was also moved to a new alignment between Ephrata and Reamstown in 1944, having previously followed State Street and Reamstown Road. This new alignment included an interchange with US 322. PA 272 was extended south from Nottingham to the Maryland border in the 1940s, replacing the southernmost section of PA 42.