The MACRO is located in the Salario-Nomentano district of Rome and occupies part of the complex that the Società Birra Peroni used for its production activities. The area located between via Reggio Emilia, via Nizza and via Cagliari was purchased by the Società Birra Peroni on 24 November 1911 and the following year - based on a project by the architect Gustavo Giovannoni - the construction of the buildings began, now occupied by the MACRO, intended for stables and warehouses. The complex represents a rare example of industrial archeology in the city.

In 1971, the Birra Peroni company ceased production in this plant, the artifacts of which were abandoned. Between 1978 and 1982, a recovery plan for the complex was launched under which it is envisaged that the Birra Peroni company will transfer a part of the complex free of charge to the Municipality, the buildings of which will be used for neighborhood services.

In 1984 the Municipality of Rome took possession of the buildings and in 1989 assigned them as the seat of the Municipal Gallery of Modern and Contemporary Art of Rome.

In 1996 the renovation works of the complex began and in 1999 the site inaugurated as the Municipal Gallery of Modern and Contemporary Art of Rome. With these works the recovery of the main front on via Reggio Emilia is completed, the load-bearing structures are consolidated and the roofs are rebuilt, the openings on the internal fronts are redefined, with a complete redefinition of the distribution. Following the recovery works, both the exhibition surfaces and the deposits of the collections proved to be insufficient.

In 2000, the Municipality of Rome announced an international design competition to respond to these needs and to the desire to redefine the image and functioning of the entire complex, with new spaces responding to the heterogeneity of contemporary artistic production, within the context of a system of relationships and connections with already existing spaces as well as with the surrounding urban space.

In 2001, the French architect Odile Decq was commissioned to build the extension of the museum, whose works started in 2004.

In 2002 the museum took the name of MACRO — Museum of Contemporary Art of Rome.

In 2010 the museum reopened to the public.

Odile Decq's intervention gives the museum a dynamic system of multiple articulations and connections. The large spaces such as the exhibition halls (which occupy a total area of 4,350 m2), the foyer, the auditorium and the terrace are connected by stairways, lifts, galleries and passages which, in addition to offering tangential perspectives and sequential viewpoints, make the experience of the museum's architecture dynamic and heterogeneous.

When the institution was still active as the Municipal Gallery of Modern and Contemporary Art (1997–2011) it was directed by Giovanna Bonasegale. The expansion works and the definite birth of the MACRO museum take place with Danilo Eccher (2001–2008). The new wing designed by Odile Decq was inaugurated under the direction of Luca Massimo Barbero (2008–2011). He was followed by Bartolomeo Pietromarchi (2011-2013). From 2013 to 2018 the museum was managed by two managers within the Superintendence: Giovanna Alberta Campitelli and Federica Pirani. From 2018 to 2019 the artistic direction was entrusted to Giorgio De Finis with the MACRO Asilo project.

Until 2017, the MACRO was part of the Musei in Comune system of the Capitoline Superintendency for Cultural Heritage.

Since 2018, the management has been entrusted to the Palaexpo Special Company, an instrumental body of Rome Capital, Department of Cultural Growth.