The Missouri State Museum houses an impressive collection of exhibits that portray Missouri's cultural and natural history in its two main exhibit halls - the History Hall and the Resources Hall. There are also exhibits with changing artifacts in the Missouri Veterans Gallery and the Foundations Gallery (state government and the State Capitol). A series of traveling exhibits can be used as educational tools by schools, civic and other groups. Interpretive staff offers various educational programs on aspects of Missouri's natural and cultural history.

The Missouri State Museum is responsible for a large collection of artifacts that consists of approximately 50,000 artifacts and objects from all aspects of Missouri cultural and natural history that have been collected since the museum's inception. The museum's collections include more than 130 Civil War flags and a large collection of World War I flags. Museum staff is currently trying to conserve these fragile textiles and have conserved approximately 45 of the flags as of 2010.

In 1919, the Missouri General Assembly designated the first floor of the east wing of the Capitol as the Missouri Soldiers and Sailors Memorial Hall and placed it under the care of the Adjutant General's office. Two year's later, in 1921, the Missouri Resources Museum was created on the first floor of the Capitol's west wing under the Resources Museum Commission, which was charged with the responsibility to collect and place on permanent exhibit examples of the products, flora and fauna of Missouri. The two museums were combined in 1923, and designated collectively as the Missouri State Museum under the management of the Resources Museum Commission. The Missouri Department of Natural Resources' Division of State Parks took over the museum in 1978.