The first attempt to set up a museum in Decin was in 1892 when the commercial association Deutscher Gewerbeverein took steps to open one modeled on the industrial arts museum in Liberec. The museum attracted few visitors with its modest collection though, and was closed several years later. Undaunted, private collectors led by Franz Werner continued to amass the antiques and other items that would later form the core of the museum collection.
In 1908 local physician Franz Just managed to convince the city council to purchase these private collections for 2,000 kronen. Two years later a city museum was opened with the cooperation of the society Tischgesellschaft Alt-Tätschen.
The First World War and post-war reality halted operations of the promising young museum for a number of years. In 1929 Count Thun-Hohenstein offered temporary space for the collection at Decin Castle, where it remained until Franz Queisser arranged to have it moved back to the original museum site in what is now Hudeckova ulice in Decin I. During the Second World War it was closed by government order, as were all other museums in the country.
The museum reopened again after the end of the war in 1945, when the collections of the Decin Municipal Museum and the Podmokly Municipal Museum were combined (Podmokly had been a separate town until 1942, with its own museum in the space currently occupied by the library building in Podmokly). A year later, the museum in Hudeckova ulice reopened to the public, one of the first in the borderlands to do so. Between 1949 and 1953 the museum collections were catalogued under the supervision of Karel Samsinak, the first true expert and natural scientist to serve in the institution.
A year after Samsinak’s arrival, the Municipal Gallery was opened. The space in Hudeckova ulice was simply not adequate, so in 1953 the institution moved to the former Thun-Hohenstein hunting chateau, which had served the forestry service to that point. The same year a local history society, Spolek pratel muzea v Decine, was formed. The group actively took part in organizing exhibits, events, and lectures, which were also published in a series of pamphlets that preceded the current journal Decinske vlastivedne spravy.
The museum first welcomed visitors in its new location in April 1955. Soon after, the adjacent park was recultivated. Further reconstruction on the building followed and in 1962, after some extensive reshuffling, the museum was given the name it goes by now, the Decin Regional Museum. In the years to come its holdings would be significantly expanded, absorbing collections from smaller museums in Ceske Kamenice, Benesov nad Ploucnice, and Sluknov.
A major exhibit on the history of Elbe water traffic opened in 1969 and that same year the museum was granted exclusive specialization for the history of water traffic for the full length of the Elbe River. For this reason, the museum holds one of the largest libraries of water navigation anywhere and owns a vast archive of photographs of watercraft, a collection of historical navigational maps of the Elbe and Moldau rivers, an exhaustive collection of blueprints and plans, and other items documenting waterborne transit and shipping.
The late 1970s saw wide-ranging reconstruction at the museum and the incorporation of two branch museums, in the northern cities of Rumburk and Varnsdorf. The new era brought many changes. Museum staff could now focus their energies on expert endeavors, in particular the deeper exploration and mapping of regional history (such as the permanent exhibit on regional Gothic statuary), regular showcases of the work of local artists and artistic groups, and a much greater focus on collection maintenance and the restoration of pieces that had been on the verge of crumbling apart. A major renovation of the museum attic and the construction of a new depository were undertaken.
In the following years, work on the museums in Decin, Varnsdorf and Rumburk has continued. In Decin the facade was refinished and the courtyard converted into a lapidarium (a statue garden). Sculptures of Saint Florian and John of Nepomuk were moved to the museum park in the 1990s. Exhibit space was expanded to include the former armory at Decin Castle, where an exhibit of historical marionettes was on loan from Milan Knizak from 1998 to 2002. Other permanent exhibits dating from this period were the Castle Armory, Gothic Art, Decin Landscapes, and Decin Castle Through the Ages. In 2002 the museum was reorganized as a funded institution under the Usti nad Labem regional authority. In 2008–2012 the museum in Rumburk was completely remodeled.
Exhibits dating from the post-revolutionary era (the period following the 1989 Velvet Revolution) include Fates in Stone – Conciliation Crosses in the Děčín Region (1994), Portrait Gallery of the Thun-Hohensteins (1998), Coptic Fabrics (1998), Czech Fine Art of the Early Twentieth Century (2003), Viennese Court and Table Silver (2003), Half-Century of the Museum (2004), Curiosities from the Museums of the Ústí Region (2005), and exhibitions dedicated to regional painters Rudolf Vejrych (2007) and Josef Stegl (2010).