Dating back to the early days of the state highway system, M-50 was first signed in the southeastern corner of the state in 1919. During the 1920s, the highway was extended to the Grand Rapids area and beyond to Lake Michigan, making it a trans-peninsular route connecting that Great Lake with Lake Erie. A rerouting of highways including M-50 through Grand Rapids in the 1950s created Business M-50 (Bus. M-50), a business loop through that city that lasted for eight years. Additional changes made during the 1960s rerouted M-50 to replace its business loop until the highway was shortened to its present western terminus south of Lowell. A pair of truncations in Monroe in 1996 and 2006 are responsible for the present-day eastern terminus.