The museum opened on February 12, 1889, thanks to the efforts of Innokenty Alexeyevich Matveev and his wife Yulia Petrovna Matveeva, the daughter of merchant Pyotr Ivanovich Kuznetsov. They were representatives of the local intelligentsia. Initially, the museum was located in the estate of Krutovskys at: Karatanova Street, house 11. Later, it was moved to the second floor of the Guest Rows on Starobazarnaya Square.

The modern building of the museum, designed in an Egyptianizing style of historicism, was created by the famous Krasnoyarsk architect Leonid Alexandrovich Chernyshev. In 1912, the Krasnoyarsk City Duma established a committee for the construction of the regional museum building, choosing Chernyshev's project. The architect agreed to develop the project for free and oversee the construction. Work began in the spring of 1914 after Ivan Ivanovich Kraft was appointed governor of the Yenisei province.

However, due to the outbreak of World War I, the building remained unfinished. For a long time, it housed barracks, and in 1920, a military hospital. In the same year, during the fumigation of the premises with sulfur, the building burned down. Repairs only began in 1927, and the construction was finally completed in 1929.

Since 1930, the museum's exhibition and collections have been in the current building designed by Chernyshev. During the Great Patriotic War, the exhibitions were suspended, and the building housed the Administration of the Northern Sea Route.

In 1987 and 2001, the museum underwent major renovations. A modern storage facility was built on the north side. In 2013, the museum's facades were restored according to the original project.

The museum's exhibition covers the history of the vast region from ancient times to the present day. The museum includes five branches and has the largest museum collection beyond the Urals. Tours are conducted in four languages: Russian, English, German, and French.