On November 15, 1890, the first meeting of the Perm Commission of the Ural Society of Naturalists took place, and this day is considered the founding date of the Perm Museum. On January 25, 1894, the museum opened its doors to the public for the first time in a building on Pokrovskaya Street, house 38, provided free of charge. In 1897, the museum moved to a renovated building on Petropavlovskaya Street, house 38.

In 1901, the Charter of the Perm Scientific and Industrial Museum was adopted, which became the successor to the Perm Commission of the Ural Society of Naturalists. In 1919, after the establishment of Soviet power, the Provincial Committee for Museums and the Protection of Monuments of Art and Antiquity was created in Perm, headed by A. K. Syropyatov. In December 1923, the museum moved to the building of the former theological seminary.

Later, the museum was provided with the buildings of the former archbishop's house, the former haberdashery store of the Central Workers' Cooperative, and the Cathedral building. The move to these premises was completed in 1931. However, in 1941, the main building of the museum, the archbishop's house on Komsomolsky Avenue, house 6, was transferred to the dormitory of the medical institute, and the museum was closed. In 1943, the building was returned to the museum, and its operations resumed.

In the second half of the 20th century, the museum actively developed, its collections were replenished, and new branches were opened. The first of these, the Memorial House-Museum "Underground Printing House," was opened on November 5, 1968.

On November 15, 2007, the Perm Regional Museum last welcomed visitors in the building on Komsomolsky Avenue, house 6, after which it began its move to the Meshkov House. On May 18, 2009, on International Museum Day, the museum reopened its doors to visitors in the restored Meshkov House.