The history of Palazzo dei Musei begins when the Franciscans settled there in 1256, transforming it into a convent. In 1798, due to the Napoleonic suppressions, the headquarters was abandoned and used as a barracks and stable. After the Restoration, the palace hosted the Royal Legal Boarding School and the Royal High School of Chemistry and Physics. Precisely the presence of scientific educational institutions led to the decision, in 1830, to set up the private collection of Lazzaro Spallanzani, then in 1862 the collection nuclei of Gaetano Chierici, the naturalistic zoology collections of Antonio Vallisneri and the Ethnography collections were set up, reorganized in 1999. The Portico dei Marmi, established in 1875 and restored in 1991, houses stone finds and epigraphs from Roman times to the 18th century. Roman architectural marbles are also exhibited outdoors in the adjacent Cloister. The Museum Atrium preserves mosaics dating back to the Roman age and the 12th and 13th centuries. The room dedicated to Roman Reggio (1996-1998) is an ideal expansion of the Chierici Collection, and includes archaeological finds from the Roman foundation of the city to late antiquity. In the naturalistic field, the collections dedicated to Geology (1989), the Fauna of the Reggio Emilia area (1992) and the exhibition of the remains of the Valentina whale (2001), a 3.5 million year old fossil cetacean found in the Secchia river valley, were added .

In 2021, the new layout of the second floor was inaugurated, which offers a narrative from the prehistory of the Reggio Emilia area to the early Middle Ages. The historical-artistic section continues from the centuries of the Este family to the First Tricolor up to the 19th century and the contemporary world, represented by the photographic heritage collected or commissioned within the European Photography project. A permanent section, with rotating exhibitions, is dedicated to the production of Luigi Ghirri.