It was the residence of Marius Dufresne and Oscar Dufresne, two wealthy French Canadian entrepreneurs who played a major role in the history of the city of Maisonneuve. The Château Dufresne was originally divided into two separate households, one for each brother. In 1948, the Dufresne family sold the property to the Congregation of the Holy Cross who used it as a pavilion annex of the Holy Cross College. In 1957, the City of Montreal became the new owner of the estate. The Holy Cross College, however, remained tenant until 1961. The mansion then housed Montreal Museum of Contemporary Art from 1965 to 1968 and Montreal Museum of Decorative Arts from 1976 to 1997. Since 1999, the building houses the Château Dufresne Museum, renamed Dufresne-Nincheri Museum in 2014.
Built from 1915 to 1918, the mansion was designed by the Parisian architect Jules Renard and Marius Dufresne in the Beaux-Arts style. The architects based their plans on the Petit Trianon in Versailles, France. The building has forty rooms covering about 20,000 square feet. The interior was decorated with a series of murals and ceiling paintings by Guido Nincheri in the 1920s and 1930s. Known for his piety and devout religious leanings, the secular subject matter of the Château Dufresne's interior decor is an exception to the rest of Nincheri's artistic career. Alfred Faniel, a Belgian born artist, also decorated the house at the same period.
The Château Dufresne was declared an historic monument by the provincial government in 1976.