The Museum der Moderne Salzburg was founded with the "Schenkung Welz", a collection of modern prints, and opened in 1983 in the early baroque palace of the former seminary "Collegium Rupertinum" in the old town of Salzburg as "Modern Gallery and Graphic Collection - Rupertinum". Founding director Otto Breicha (1983―1998) expanded the collection by buying Austrian photography. In this part of the collection, known as the "Austrian Photo Gallery", holdings of the federal government are also administered. Under the direction of Director Peter Weiermair (1998―2001), the program of the Rupertinum has become more internationally oriented.
In the 1990s, spectacular plans for a Guggenheim Museum Salzburg in the rock of the Mönchsberg were forged, which were ultimately not realized. Finally, a new building for a "museum of modernity" was erected on the Mönchsberg, where the Café Winkler was previously located. In 2004, under the direction of Agnes Husslein (2000―2005) opened the Museum der Moderne on Mönchsberg. In the 2000s, the house was brought closer to contemporary art, which has for some time been the focus of the program. Under director Toni Stooss (2005―2013), a prominent painting by Gustav Klimt was restituted to the rightful owners. With a portion of the sales proceeds generously donated by the owners, the former water tower on Mönchsberg was upgraded. Since 2014, the significant building, henceforth referred to as the "Amalie-Redlich-Turm", is operated as a center for art education with an artist studio apartment.
Director Sabine Breitwieser (2013―2018) successfully re-profiled the museum. Large solo exhibitions have been dedicated to important female artists, and non-Western artists have been increasingly included in the program. In 2014, the Museum der Moderne Salzburg was able to enter into a comprehensive partnership with the Generali Foundation, and its long-standing international and high-quality collection was won on permanent loan. With the partial renovation of the Rupertinum 2016 and the construction of the new art storage unit in 2017, important improvements to the infrastructure of the museum were realized.
Since September 2018 Thorsten Sadowsky is the new director of the Museum der Moderne Salzburg. He defines the museum as a discussion forum that draws its legitimacy from a critical location of past and present. The exhibition spectrum ranges from classical modernity to conceptual art, light and sound art to media art and to current positions in non-European art. The Museum der Moderne Salzburg is to be positioned in the sense of a comprehensive pictorial scientific term as an international competence center for art, photography and visual cultures.