The museum was created in 2016 following three decrees by the Minister for Cultural Heritage and Activities and Tourism, Dario Franceschini.

[7] Initially, the Museum of Civilisations was intended as a "museum of museums",[8] maintaining a formal distinction between the six institutes and naming them after their respective founders or in any case significant figures for their areas of expertise (respectively Luigi Pigorini, Lamberto Loria, Alessandra Vaccaro, Giuseppe Tucci, Ilaria Alpi and Quintino Sella).

These criteria, however, were changed in 2022 under the directorship of Andrea Viliani, who took office at the beginning of the year and proposed a different approach by promoting the integration of the collections with an interdisciplinary perspective, and the creation of a modern anthropological museum.

[9][10] The museum is housed in two rationalist-style buildings, connected by an imposing colonnade and designed – like the entire EUR district – to host the 1942 Universal Exhibition E42 ("Esposizione 1942"), which never took place due to the outbreak of the Second World War.

[4] The Prehistory and Ethnography Museum and the Museum of the Early Middle Ages have been located since 1967 in the contemporary Palace of Sciences (Palazzo delle Scienze), originally designed and built to host the Universal Science Exhibition ("Mostra della scienza universale") during E42.