The Museum building, located among a group of Assyrian houses north of the Republic Square on the First Street in the Şar Quarter of Mardin Center, was built in 1895 by the Patriarch of Antakya Ignatios Behnam Banni as the Assyrian Catholic Patriarchate, according to the inscription on the closed portrait of the Virgin Mary Church, which is adjacent to the eastern side of the building facing the Museum. The building, which served religious purposes for a long time, was later used as a military garrison, the headquarters of various political parties, a cooperative building, a health center and a police station.

The Ministry of Culture purchased the building from the Syriac Catholic Foundation, restored it and moved the Mardin Museum from Zinciriye Madrasa to this building in 2000. Due to the slope of the land in the area where the museum building is located and the depth of the parcel, the design was realized as three floors in the form of terraces. Serving since 1947, the Mardin Museum is also remarkable for the variety of artifacts in its collection.

Since there are no museums in provinces such as Şırnak, Batman and Siirt, the museum, which continues to work to protect and exhibit the artifacts in these provinces, exhibits artifacts covering the periods from the Paleolithic Age to the 19th century AD. The museum has three indoor exhibition halls and two open exhibition areas.