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 as envisioned by Angus G. Wynne. The park was divided into six themed sections: the namesake "Six Flags" over Mid-America:

On June 5, 1999, the 12-acre Six Flags Hurricane Harbor water park opened, adjacent to the main park. At a cost of $17 million, it was the largest single investment in Six Flags St. Louis' history.

In 2014, Six Flags sold 180 acres of unused land to the east of the park to developer McBride & Sons, effectively reducing the total property area of the park from 503 acres to 323 acres. According to the Six Flags 2015 Annual Report, the park now owns 323 acres of land (with 283 acres of land used for the park, plus an additional 40 acres of undeveloped land).

In January 2020, construction began on a renovated entry plaza, removing the original ticket booths that had been at the park since its opening in 1971. Subsequently, in March of the same year, Six Flags St. Louis announced that the opening of their 2020 season would be delayed, due 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, alongside six other park properties to EPR Properties. Upon completion of the sale, which is expected to be by the first or second quarters of 2026, the park will be operated by Enchanted Parks. It will retain its Six Flags branding for the rest of the 2026 season. Under Enchanted Parks, Six Flags St. Louis will be renamed Mid-America by Enchanted Parks, a reference to the park's original name Six Flags Over Mid-America.