The museum was established in 1920 by Cyrus S. Eaton to perform research, education and development of collections in the fields of anthropology, archaeology, astronomy, botany, geology, paleontology, wildlife biology, and zoology.

[4] Donald Johanson was the curator of the museum when he discovered "Lucy," the skeletal remains of the ancient hominid Australopithecus afarensis.

[5] At the end of the following year, the museum moved to a mansion on Euclid Avenue, a part of Cleveland's millionaires' row.

[11] An 85,000 square feet addition in 1972 enlarged the museum, adding galleries, the Murch Auditorium, the Harold T. Clark Library and Rare Book Room, classrooms, a paleontology laboratory, and the front entrance and lobby.

[5] In 1973, curator Donald Johanson joined an archeological expedition in Ethiopia, where he discovered "Lucy," deemed one of the most important fossil finds in human evolutionary studies.

Designed by Cleveland architectural and engineering firm Westlake Reed Leskosky (now DLR Group), the building exterior functions as an astronomical instrument.

The building's titanium-coated, stainless-steel outer covering sparkles with stars created by embedded fiber-optic lighting.

[12] On June 24, 2021, a groundbreaking ceremony took place for an expansion as part of the museum's Centennial Transformation Project.

[13] The design is said to evoke the melting ice that made the Great Lakes region and the impact of water on the communities.

[21][22] Dynamic Earth, Evolving Life, and several other renovated exhibition halls opened on December 13–15, 2024,[23][24] two years ahead of the original schedule.

A new ceratopsian, Albertaceratops nesmoi, was named in 2007 by former CMNH curator of Vertebrate Paleontology Michael Ryan.

Its administration was taken over by T. Wingate Todd after Hamann was named dean of Western Reserve University's medical school in 1912.

[citation needed] The Ralph Perkins II Wildlife Center and Woods Garden presented by KeyBank, which includes live animals and plants native to Ohio, opened on September 3, 2016.