Barcelona City Council, following Marès' will, agreed to create the Museum and locate it in the Gothic Quarter. In 1946 the first room was opened and in 1948 the center was officially inaugurated.

The Museum was arranged by taking advantage of a series of buildings that occupied part of the spaces of what had been the Palau Reial Major, seat of the counts of Barcelona and kings of the Catalan-Aragonese crown in medieval times. The medieval-style restoration of some of the outbuildings of the new museum center, coinciding with the renovation campaigns of the Gothic Quarter, gave the collections a particular setting.

The Museum is currently accessed through the patio, the garden of the aforementioned Palau Reial Major, from Plaça de Sant Iu, next to the cathedral.

Once the Museum opened, Frederic Marès did not abandon his passion for collecting and continued to acquire pieces that allowed him to increase and round out collections already on display, or start new ones. This fact, along with donations from private individuals or public or private institutions, necessitates several extensions to the building.

At the end of 1948, the official inauguration took place of four rooms that occupied the first building, which was entered from Carrer dels Comtes de Barcelona. The expansion and conditioning works continued until 1970, the year in which the Museum acquired its current architectural volume.