In 1953 Busch convinced the board of directors of the St. Louis-based brewery Anheuser- Busch to purchase the hometown Cardinals and renovate Sportsman's Park. Busch became president and chief executive officer of the team and rose to become one of the National League's most powerful owners. In the 1970s, when developers ran out of funds while building the new downtown stadium, he raised the final $3 million and the park was named Busch Stadium.

Referred to at his death as "the last of the old-time beer barons," Busch began working for his father, August Anheuser Busch, Sr., at the brewery started by his grandfather, Adolphus A. Busch, and Eberhard Anheuser. Control of the company passed to Gussie and his brother, Adolphus III, in 1934, and solely to Gussie on his brother's death in 1946. Busch built the ailing company into the largest brewery in the world by the time he retired from an active role in 1975. The brewery's ownership of the Cardinals led the team organist to use the Budweiser theme, and before each home game a team of Clydesdales, the symbol of Budweiser Beer, paraded around the playing field.