Most Blessed Sacrament parish was established in 1905 in what was then the northern city limits of Detroit. The parish was initially plagued with financial problems. Construction of the church started in 1913, but proceeded rather slowly. The interior was finished in 1930, with the dedication of the interior on Thanksgiving of that year. Detroit was elevated to an archdiocese in 1937, and Most Blessed Sacrament was chosen to be the cathedral church replacing St. Patrick's which served as cathedral since 1877. However, construction of the exterior, including the twin towers on the west facade and the flèche at the crossing, was not completed until 1951, coinciding with the 250th anniversary of Detroit's founding. The consecration on November 17, 1951, was broadcast live on local television. Plans also called for spires topping the towers, however these remain unbuilt.
In 2001, Gunnar Birkerts was selected to update the cathedral. Changes included a plaza on the north side of the structure, reconfigured interior spaces, a new sanctuary, cathedra, baptismal font and organ. The original organ was installed the west gallery by Casavant Frères in 1925 as a gift from Frederick Fisher of Fisher Body. During the renovations, this three manual/55 rank instrument was updated and a second organ was installed in the apse.
The new organ is opus 2785 of Austin Organs, Inc. with two manuals and 32 ranks and is connected to the gallery organ allowing them to be played as one instrument from the new console. The new organ was first played at the rededication ceremony March 25, 2003.
Although Pope John Paul II's 1987 visit to the United States was originally included only stops in the southern and western parts of the country, Detroit's cardinalarchbishop, Edmund Szoka, campaigned for him to include the Detroit area. Szoka made a direct request to the Pope during a visit to the Vatican City. The Pope arrived in Detroit on September 18, 1987, and spoke before large crowds in Hamtramck, Hart Plaza and the Pontiac Silverdome. During John Paul II's visit, he visited guests at the cathedral and lodged at the adjacent archbishop's residence.