Professional baseball began in St. Louis with the inception of the Brown Stockings in the National Association in 1875.

George Bradley, nicknamed "Grin", pitched for the St. Louis Brown Stockings in the club's victory over the Hartford Dark Blues on July 15, 1876. The score ended 2-0 without a hit being allowed by Bradley. That year, he completed 63 of St. Louis' 64 games, winning 45 and leading the league with a 1.23 earned run average. He also threw 16 shutouts, setting a record that has never been broken.

Jose Oquendo played all nine positions during his major league career with the Cardinals and was nicknamed "The Secret Weapon" by manager Whitey Herzog. He even recorded a decision as a pitcher, losing in a 19 inning marathon to the Atlanta Braves.

Rickey was instrumental in breaking Major League Baseball's color barrier by signing black player Jackie Robinson (while with the Dodgers). He also created the framework for the modern minor league farm system, encouraged the Major Leagues to add new teams through his involvement in the proposed Continental League, and introduced the batting helmet.

The NL expelled St. Louis from the league after 1877 due to a game-fixing scandal and the team went bankrupt. Without a league, they continued play as a semi-professional barnstorming team through 1881.

As the leadoff hitter for St. Louis, Coleman helped the team reach the 1985 playoffs. But he suffered an injury prior to the fourth game of the National League Championship Series, when the automatic tarpaulin rolled over his leg during routine stretching exercises. The injury sidelined him for the rest of the postseason, and the Cardinals eventually lost a seven-game World Series to Kansas City.

Hornsby is regarded as one of the best hitters of all time. He had 2,930 hits and 301 home runs in his career; his career batting average of .358 is second only to Ty Cobb, at .367, in MLB history.

In 1953 the Anheuser-Busch brewery (headquartered in St. Louis, Missouri) bought the Cardinals and August "Gussie" Busch became team president.

Dean finished the 1934 season with 30 wins, the only NL pitcher to do so in the post-1920 live-ball era. After his playing career, "Ol' Diz" became a popular television sports commentator.

He led the National League in stolen bases for a record eight times and also had a record twelve consecutive seasons with 50 or more stolen bases.