When Pennsylvania legislated routes in 1911, the portion of road between Weissport and Lehigh Gap was designated as part of Legislative Route 163, which ran from Allentown to Mauch Chunk (present-day Jim Thorpe) while the portion of road between Bath and Easton was designated as part of Legislative Route 175, which continued west from Bath to Northampton and up the Lehigh River to Walnutport. With the creation of the U.S. Highway System in 1926, the road between Weissport and Lehigh Gap was designated as part of US 309, a route that ran from Philadelphia north to Wilkes-Barre. In 1927, PA 45 was designated concurrent with US 309 on the road between Weissport and Lehigh Gap and onto the route of Legislative Route 175 between US 309 in Lehigh Gap and US 22 in Easton. A year later, PA 45 was shifted to a more direct alignment between Lehigh Gap and Bath. By 1930, a portion of PA 45 northwest of Bath was paved, with the section between Lehigh Gap and east of Walnutport under construction. PA 45 followed Northampton Street into Easton, where it ended at US 22 at the intersection of 13th and Northampton streets. US 22 continued along Northampton Street east of this intersection while US 22 Byp. was designated to bypass downtown Easton to the north along Prospect Avenue, Pearl Street, and Bushkill Street. US 22 was realigned to replace US 22 Byp. along Prospect Avenue, Pearl Street, and Bushkill Street in the 1940s.