 M-21 was designated by July 1, 1919 on a routing from Ionia to Goodells. Along the way, it ran through Lyons and Pewamo, joining its current routing to Ovid. M-21 continued through Corunna to Lennon and Flint. There it joined its last routing between Flint and the Port Huron area. The highway was extended to Port Huron by 1924, and the west end was extended to Grand Rapids in 1925 along M-16 (later US 16). The previous routing through Owosso and Lennon was redesignated as M-71 at this time when M-21 was shifted along the current routing between the two communities. The 1926 creation of the United States Highway System led to the extension of M-21 along US 16 to Grand Rapids. From there west, M-21 replaced M-51 on Chicago Drive to Holland. The highway was moved to a new routing between Flint and Lapeer in 1929; the old route was renumbered M-21A. All in-city portions of M-21 were transferred to state control in 1931 with the passage of the Dykstra Act of 1931 (PA 131 of 1931).
