The museum traces its starting point to the Panama–California Exposition, which opened in 1915 on the occasion of the inauguration of the Panama Canal.

[1] Hewett organized expeditions to gather pre-Columbian pottery from the American Southwest and to Guatemala for objects and reproductions of Mayan civilization monuments.

[1] During World War II, the museum underwent conversion into a hospital, necessitating the temporary storage of its exhibits and collections.

Post-war, the institution shifted its focus to the people of the Western Americas, eventually leading to significant growth in its collections from the 1980s through the early 1990s.

[5] On the opposite (south) side of the California Quadrangle, housed in what was originally the Fine Arts Building, is Evernham Hall, a banquet room that is also used for temporary exhibits.

The museum also holds a collection of Ancient Egyptian antiquities, including burial masks, figurines, and seven painted wooden coffins; one piece is a Ptolemaic child's coffin—only six others are known to exist worldwide.

The California Building and its tower were used by Orson Welles as the principal features of the fictitious Xanadu estate in the classic film Citizen Kane.