The museum opened on October 29, 1988, organized around four themes: art, cultural history, science and technology, and natural history. Among the first things visitors meet is a life-size replica of the Best Friend of Charleston, the first American-built locomotive, which ran in 1830. Nearby hangs another replica, the H. L. Hunley - the Civil War submarine that became the first underwater vessel to sink an enemy ship in combat. Both built in South Carolina, both representing moments when this state stood briefly at the front edge of technology and at terrible cost. The Hunley sank shortly after its successful attack, killing its eight-man crew.

Round a corner on the natural history floor and you may not look up in time. Suspended overhead is Finn, a recreation of a megalodon, the 3.6-million-year-old shark whose teeth still wash out of South Carolina riverbeds. Down the corridor stands a life-size Columbian mammoth, a species that once roamed what is now the Carolina Piedmont, browsing on grasses that no longer grow here. The first natural history curator at the museum was Rudy Mancke, who went on to produce NatureScene for South Carolina Educational Television - a program that ran nationally for years, teaching generations to look closely at common things.

Tucked inside the same mill is the South Carolina Confederate Relic Room and Military Museum, established in 1896 - the oldest museum exhibit in Columbia. Down on the first floor, the Lipscomb art gallery features an iron gate forged by Philip Simmons, the Charleston blacksmith whose ornamental work shapes much of that city's most beautiful private architecture. The parking lot contains topiary sculpted by Pearl Fryar, the self-taught Bishopville artist whose garden became a National Register site. A 1989 mural by Columbia's Blue Sky depicts the Gervais Street Bridge a few hundred yards away. The museum is, in many ways, a directory to South Carolina's other artistic and scientific landmarks.

The traveling exhibitions catalog reads like a half-century of public fascinations. King Tut came in 2003 and again in 2013. Body Worlds Vital arrived for the centenary of the Titanic in 2012. Leonardo da Vinci's notebooks came in 2008. In 2017, for the total solar eclipse that crossed Columbia, the museum's observatory hosted thousands. In 2019, for the fiftieth anniversary of Apollo 11, the museum borrowed personal items from Charles Duke - the South Carolinian who walked on the moon as Apollo 16 lunar module pilot in 1972. In 2020, the Sherlock Holmes exhibit arrived from the Museum of London with manuscripts and props. The 4D theater and digital dome planetarium, added in 2014, give the museum the toys of a science center alongside the artifacts of a state archive.