Established in 1927, US 19 traversed from the Georgia state line (at Bellview) to the Tennessee state line (at Elk Park), roughly similar to the route seen today. In 1930, US 19 was truncated at Cane River, where it was split into US 19E and US 19W; US 19E follows the original US 19 routing north. In 1932, it was rerouted in Asheville from Haywood Road to Clingman Avenue, to Hilliard Avenue to Biltmore Avenue toward Broadway Street. In 1937, US 19 was rerouted south of Almond to its current alignment today; while it was rerouted through downtown Asheville again: from Haywood Road to Clingman Avenue to Patton Avenue to College Avenue to Biltmore Avenue toward Broadway Street.
In the 1940s, additional construction work on US 19 was assured by a compromise made with the Eastern Band of Cherokee Indians in return for right-of-way through the Qualla Boundary for the Blue Ridge Parkway.
In 1947, US 19 was rerouted from Ela, traversing through Dillsboro, Sylva, and Waynesville, to Lake Junaluska. The old route, through Cherokee and Maggie Valley became US 19A. In 1948, it was switched, having US 19 back along the original route and US 19A going south to Lake Junaluska.
In 1949, US 19 was moved onto the Smokey Park Highway/Patton Avenue as a bypass in western Asheville. The old alignment became US 19A (today's US 19 Business, or US 19 Bus.). In 1952, US 19 was rerouted off Martins Creek Road and onto Blairsville Highway, near Ranger. In 1954, US 19 was realigned to its current route from Lake Junaluska to Clyde and Canton; 0.5 miles (0.80 km) of the old route was replaced by NC 209. Between 1955–1957, US 19 was split onto one-way streets in downtown Asheville: northbound used Patton, to Market, to Woodfin, to Broadway, and southbound used Broadway to College, to Patton. In 1961, US 19 removed from downtown Asheville and put on the East–West Expressway, north at Marrimon Avenue. Between 1963–1968, US 19 was split onto one-way streets in downtown Canton (Park Street and Main Street). In 1961, US 19 was moved onto new freeway west of Weaverville; the old route became US 19 Bus.