Also known as “Matty” and “Big Six,” he pitched in the National League for the New York Giants from 1900 to 1916 and for the Cincinnati Reds in 1916; he also managed Cincinnati from 1916 to 1918. From 1923 until his death he was president of the Boston Braves in the National League.

Mathewson was one of the first college men to enter the major leagues, having been a football and baseball player at Bucknell University, Lewisburg, Pa. For the Giants he won more than 20 games in each of 13 seasons (12 consecutive, 1903–14) and 30 or more on 3 or 4 occasions (29 or 30 in 1903; many old baseball records are in dispute). In 1908 he scored 35 or 37 victories, 11 or 12 of them shutouts. He won 367, 372, or 373 regular-season games in his career while losing only 186 or 188. In four World Series he won five games, pitching three shutouts against the Philadelphia Athletics in the 1905 Series and another shutout against the Athletics in 1913.

A right-handed thrower and batter, Mathewson was a master of the fadeaway pitch, later called the screwball. Testifying to the pitcher's exceptional control, a Giants' catcher said he could “catch Matty in a rocking chair.” Mathewson was an intelligent, proud, reticent man with great powers of concentration.