In the late 19th century, the Evangelical Lutheran Synod of Michigan felt a need to train pastors to serve a growing number of congregations. They recognized the value of training their own pastors so that they would continue to have well-trained confessional pastors.

Michigan Lutheran Seminary began in 1885 with one teacher and six students assembling in Manchester, Michigan. In 1887, Pastor Christoph Eberhardt of St. Paul’s congregation in Saginaw donated two near-by acres of land on Court Street. The Michigan Lutheran Synod moved MLS to this newly donated land, which became its present location. They dedicated the school's first building, Old Main, later that year. Pastors Lange, Huber, Hoyer, Linsemann, and Beer led the school from 1887-1907 as a pastoral seminary.

In 1892, Michigan, Wisconsin, and Minnesota Lutheran Synods joined together in a confederation. Plans were submitted to convert MLS from a pastoral training seminary into a preparatory school for the new confederation. This brought about a disagreement that ended up with the withdrawal of the Evangelical Lutheran Synod of Michigan departing. MLS continued as a pastor-training seminary until dwindling enrollments forced it to close its doors in 1907.

In 1910, the Evangelical Lutheran Synod of Michigan rejoined the confederation. Again it was decided to proceed converting the pastoral training seminary at MLS into a “progymnasium,” or preparatory school, for the college in Watertown, Wis., (now Martin Luther College in New Ulm, Minn.) and then the seminary in Wauwatosa, Wis., (now Wisconsin Lutheran Seminary in Mequon, Wis.). The name Michigan Lutheran Seminary was kept to call to mind the original purpose of the school. The confederation called Pastor Otto J. R. Hoenecke to reopen Michigan Lutheran Seminary as this new preparatory high school.

Since reopening on September 13, 1910, Michigan Lutheran Seminary has continued to fulfill its mission and purpose “to prepare high school students for the public ministry of the gospel, encouraging them to enroll in the WELS College of Ministry, Martin Luther College.”