The museum opened on October 29, 1988, and is housed in what it calls its largest artifact: the former Columbia Mills Building, listed on the National Register of Historic Places in 1982.

The second floor on natural history is notable for its recreation of a 3.6-million-year-old megalodon, named Finn, suspended mid-air just around a corner, and for a life-size Columbian mammoth (which was once native to SC).

The Museum's first natural history curator was Rudy Mancke, who went on to produce a national program on South Carolina Educational Television called NatureScene.

Travelling exhibitions at the State Museum have included "Spanish Explorations in the Caribbean and the US, 1492-1570" (for the 500th anniversary of Columbus' discovery) in 1990, WWII and SC in 1991 (for 50 years since the Pearl Harbor attack), "Rock, Roll, and Remember: Hootie & the Blowfish and Other SC Greats" in 1997, The World of Insects in 1998, Star Trek: The Exhibition in 1999, The Magic School Bus in 1999, Inside Africa in 2004, Prehistoric Predators in 2004, Napoleon Bonaparte in 2006, Aliens: Worlds of Possibilities in 2007, Leonardo da Vinci in 2008, a 2008 exhibit on several of the movies (like The Patriot and Forrest Gump) filmed in SC ("Hollywood Comes to South Carolina"), "Football in the Palmetto State, 1889-2000" in 2008, Pirates in 2010, 150 years of the Civil War in SC in 2011, Body Worlds Vital in 2012, Titanic: the Artifact Exhibition (100 yr. anniversary) in 2012, Secrets of the Maya in 2012, King Tut in 2003 and 2013, Dinosaurs: A Bite Out of Time in 2014, Julius Caesar: Roman Military Might in 2015, "RACE: Are We So Different?"

in 2016, Savage Ancient Seas in 2017, the 2017 Solar Eclipse in Columbia exhibit in the observatory, The Wizard of Oz in 2017 for Halloween, Hall of Heroes (superheroes) in 2019, 50 Years of the Apollo 11 Moon Landing (with items from SC astronaut Charles Duke) in 2019, and Sherlock Holmes: the International Exhibition in 2020 (with items from the Museum of London).