When the state highway system was first signed in 1919, M-50 started at an intersection with M-23 (present-day US 12) in Cambridge Junction, south of Brooklyn. From there it ran to the southeast, similar to its present-day routing, through Dundee and Tecumseh into downtown Monroe where it intersected M-56. There was a concurrency between M-50 and M-65 between Dundee and the Ida area which became an overlap with US 23 after 1926. By the end of 1927, M-50 underwent a major lengthening as its western terminus was extended through Jackson to Eaton Rapids, Charlotte, and Vermontville before intersecting M-39 just east of Woodbury. From this point, M-50 was routed over M-39 to US 16 near Alto. M-50 then ran concurrently with US 16 into Grand Rapids where it turned to the west and traveled through Allendale before terminating at a junction with US 31 in Agnew. A few years later in 1929, the route between Charlotte and Woodbury was changed as M-50 was routed north out of Charlotte to the former M-39 and replaced it east to Woodbury; the former routing was turned over to local control.