Plans for a Six Flags park in the St. Louis area—dubbed Six Flags Over Mid-America—were announced on July 16, 1969. The park opened on June 5, 1971, the third and last of the three "true" Six Flags parks envisioned by Angus G. Wynne. The park was divided into six themed sections, each under one of the "Six Flags":

The park's name was changed to Six Flags St. Louis for the 1997 season. On June 5, 1999, the 12-acre Six Flags Hurricane Harbor water park opened next to the main park, a $17 million expansion that was the largest in the park's history.

In 2014, Six Flags sold 180 acres of unused land to the east of the park to developer McBride & Sons, reducing its property area to 323 acres: including 40 acres of undeveloped land.

In January 2020, a renovation to the entry plaza removed the original ticket booths. That March, Six Flags St. Louis announced that the opening of their 2020 season would be delayed by to the COVID-19 pandemic.

Yearly attendance figures have not been released.

On March 5, 2026, the park's owner, Six Flags (which had merged with Cedar Fair in 2024), announced that it would sell Six Flags St. Louis and six other park properties to EPR Properties. The sale was completed on April 6, 2026. EPR hired Enchanted Parks to operate the park. It will retain its Six Flags branding for the rest of the 2026 season, then be renamed Mid-America by Enchanted Parks.