Born in in Mainz, Germany in 1839, Busch emigrated to St. Louis in 1857, working as a clerk on the riverfront and in the wholesale supply business. Two years later, he received an inheritance from his father´s estate and formed a partnership with Ernst Wattenberg for a brewers´ supply business. Busch married Eberhard Anheuser´s daughter, Lily, in 1861. Following his service in the Union Army during the Civil War, he returned to St. Louis in1866 and joined his father-in-law´s company, Anheuser´s Bavarian Brewery, as a salesman. Within five years of joining the struggling brewery, Busch had doubled its capacity. In 1879, he became a partner and the brewery’s name was changed to the Anheuser-Busch Brewery. A year later, Anheuser died, and Busch became president. Under his leadership, the brewery marketed 19 different brands of beer, including Budweiser, America’s first national beer, and Michelob, introduced in 1896 as a "specialty beer for Connoisseurs". In 1901, for the first time, Anheuser-Busch brewed more than 1 million barrels in a single year and became America’s largest brewer. Anheuser-Busch also shipped products to 125 markets in 44 countries on six continents.

A visionary in many ways, Mr.Busch foresaw the encroaching shadow of Prohibition. To bolster beer’s image, Anheuser-Busch began using the "true temperance beverage" theme in its printed catalogues as early as 1889. In addition, at his direction, the brewery began developing nonalcoholic beverages. Busch was also a leading civic benefactor, contributing the funds to erect the Naked Truth statue, and providing $100,000 to build Busch Hall at Washington University. He was also president of the South Side Bank.