The origins of the museum go back to 1879, the year in which the institution made its first acquisitions.

In its earliest days, it was under the direction of Abbé Pierre Girard, then Abbé Pierre-Achille Bégin. The Museum grew rapidly between 1900 and 1969 under the direction of Canon Léon Marcotte. He gave a large part of his life to building the museum and left a heritage of tens of thousands of collection objects and specimens.

The Museum closed its doors after the death of the Canon in 1969. In 1973, Monsigneur Georges Cloutier re-opened the Museum by creating the Corporation du Musée du Séminaire de Sherbrooke. In 2002, this new entity took its place in a new building where today the Musée de la nature et des sciences de Sherbrooke is located.