Busch began working for Anheuser-Busch in 1924. He became president of the company in 1946, was elected chairman of the board in 1956, and chief executive officer in 1971. Under his leadership, the company built eight regional breweries, increased its annual sales from 3 million barrels in 1946 to more than 34 million in 1974, and began diversifying into family entertainment, real estate, can manufacturing and transportation.

Busch was also an active and visible civic leader. He served as president of the St. Louis Bicentennial Corporation, which planned the celebration of the 200th anniversary of the founding of St. Louis. He spent 13 years as chairman of the board of Civic Progress, a non-profit organization of civic leaders devoted to revitalization of the St. Louis area. He also was Chairman of Saint Louis University`s successful $18,000,000 Development Fund Drive. He is perhaps best known for his purchase of the St. Louis Cardinals baseball team in 1953, a move that saved the team from an imminent move to Milwaukee or Houston. Busch bought the team and his love of baseball was evident throughout the years that he owned it, highlighted by his entering the stadium every opening day on top of his Clydesdale draw carriage.

Busch also served with distinction in the U.S. Army Ordinance Department, where he was commissioned a major. He retired from active service with the rank of colonel. For his wartime service, he received several citations and the award of the Legion of Merit.