PA 272 was first designated in 1928 to run from US 222/PA 72 in Wakefield east to US 1/PA 12 in Nottingham. The route was fully paved by 1940. In the 1940s, PA 272 was extended south from Nottingham to the Maryland border, replacing a section of PA 42 between the Maryland border and Chrome. The route was extended north from Wakefield to US 222 in Willow Street in the 1960s. This extension replaced what became a southern extension of PA 72 from Lancaster in the 1930s. The route was extended from Willow Street to US 222 and PA 568 in Adamstown following the completion of the US 222 freeway between Lancaster and Adamstown in 1977. PA 272 followed US 222 through Lancaster and ran along the former alignment of US 222 between Lancaster and Adamstown. In 2006, the intersection at the northern terminus was converted to an interchange following the extension of the US 222 freeway from Adamstown to the Reading area.