Charles Henry Genslinger came to St. Louis in 1903, when the city was preparing for the 1904 World’s Fair and the Summer Olympics. He persuaded local prominent citizens to establish a private amateur athletic and social club, similar to those he had organized in New York City and New Orleans. More than 3,200 members enrolled prior to the Missouri Athletic Club (MAC) opening its doors on 13 September 1903. The club’s mission was to be the premier athletic, dining, and social club for business, professional, and civic leaders and their families in the St. Louis region. The MAC has changed its name through the years, including St. Louis Athletic Club and Missouri Athletic Association (1916-1939). In 1988, the club’s membership voted overwhelmingly to admit female members. In 2000, the MAC was awarded "Platinum Club" status, a distinction awarded to only 150 of the more than 5,000 private clubs across the country.

In 1903, Boatman's Bank donated a seven-story building at Fourth Street and Washington Avenue in downtown St. Louis to the Missouri Athletic Club. In 1914, the clubhouse was completely destroyed by a fire, which also killed thirty members, guests, and staff. The MAC decided to construct a new building in its place. The present-day downtown clubhouse opened its doors on 1 March 1916, with a gala celebration attended by 5,000 people. The new clubhouse, a ten-story facility, was grander than the original building. In May 2007, it was added to the National Register of Historic Places. In 1995, the club purchased the former Town and Country Racquet Club in suburban St. Louis in order to offer more programs like tennis and outdoor swimming.

Upon its founding, the MAC joined the Amateur Athletic Union (AAU), which allowed members to participate in boxing, wrestling, water polo, swimming, and track at the 1904 Summer Olympics. In subsequent years, this AAU membership allowed basketball, swimming, track, baseball, boxing, wrestling, bowling, and billiards teams formed at the MAC to compete throughout the United States. In 1987, the MAC began awarding the Hermann Trophy, the highest award in college soccer, to the top U.S. male and female players.

In addition to athletics, the Missouri Athletic Club offers its members several options to socialize, travel, and improve in sports, hobbies, and other specific interest areas. The Clubs Within the Club (CWC) includes groups for dance, wine, books, bridge, business development, and several others. Founded in 1943, the Apollos are the longest established CWC at the MAC with music, good fellowship, and community service among the rewards for participants.