The Saint Louis Science Center traces its roots to the Academy of Science of St. Louis, founded in 1856 as the first scientific organization west of the Mississippi River. In 1959, the Academy created the Museum of Science and Natural History in Clayton's Oak Knoll Park. When the Metropolitan Zoological Park & Museum District (ZMD) was formed in 1971, the Museum of Science and Natural History became a member, independent from the Academy, which continues to operate as a separate entity to this day.
The Museum then outgrew the facilities at Oak Knoll Park in the mid-1980s and, in 1984, the Museum acquired the James S. McDonnell Planetarium from the City of St. Louis. After extensive renovations, the Planetarium reopened in 1985 as the Saint Louis Science Center.
Following a $34 million expansion to construct the current main building on Oakland Avenue, the Science Center opened November 2, 1991, in its larger footprint including the five story OMNIMAX Theater and a highway-spanning connection bridge. The Science Center added the EXPLORADOME in 1997 in order to provide an additional space for large traveling exhibitions. With the popularity of the EXPLORADOME, the Science Center took action to create a permanent exhibition space. In October, 2011 Boeing Hall opened dedicating 13,000 square feet of exhibit space for traveling exhibitions.
The Saint Louis Science Center was named a Smithsonian Institution Affiliate, the first in the St. Louis area in 2016. This title provides access of Smithsonian artifacts, traveling exhibits, and educational collaborations locally and nationally.