Anson played in the National Association, the first professional baseball league, with the Forest City team of Rockford, Illinois, in 1871 and with the Philadelphia Athletics (1872–75). He is believed to have batted .352 during those five years. In 1876, when the Chicago National Association team—the White Stockings, later known as the Cubs—switched to the newly formed National League, Anson joined this club, and in 1879 he became its manager. Anson, who played first base for most of his career, was credited with batting championships in 1879, 1881, and 1888. His total number of hits in the National League is given as 2,995 or 3,081 (authorities differ), and thus his National League career batting average is either .329 or .339; it is certain, however, that Anson was the first player to get 3,000 lifetime hits.

Anson retired as a player and resigned as Chicago manager after the 1897 season and was nonplaying manager of the New York Gothams (later known as the Giants) in the National League in 1898. As a manager Anson led Chicago to five National League championships. He was, however, profoundly opposed to integration within professional baseball and is thought to have been one of the major forces behind the “gentlemen's agreement” that barred black players from being signed to major league teams.

He was elected to the Baseball Hall of Fame in 1939.