The hotel was opened to the public for the first time on April 2, 1904, for a charity ball sponsored by the St. Louis chapter of the Daughters of the Confederacy and the Confederate Memorial Society.

During the late 1930s, Max Theodore Safron (d. 1980) operated his art gallery from the Jefferson Hotel's mezzanine, where he primarily sold American, British, and French paintings to the city's wealthy clientele.

[4] In 1952, Hilton gutted and modernized many of the hotel's surviving historic interiors, including the main lobby, dining room and coffee shop, and added a 24-hour drug store/soda fountain.

[11] The new owners announced plans to convert the enormous building to a combination of 239 apartments, a 198-room AC by Marriott hotel, and 20,000 sq ft of retail.

[12] In February 2021, Alterra paid over $100,000 in back taxes owed on the property, clearing the way for $17.3 million in financing from the city of St. Louis.

[13] In October 2022, following the settlement of a lawsuit by the carpenters' union,[14] Alterra announced slightly adjusted plans, for 225 hotel rooms and 235 apartments, with work set to begin in the near future.