Born into a wealthy family in Factoryville, Pennsylvania, Mathewson attended Bucknell University, but immediately after graduation signed with the New York Giants. Extremely intelligent, he was a master player of American checkers and once defeated the World checkers champion.

The dominant pitcher of his era, Christy Mathewson won more than 20 games for twelve straight years, including winning 30 or more games for three seasons in a row between 1903 and 1905. In 1908 he won 37 games, a National League record that still stands. A master craftsman, "Matty" was well known for a screwball-type pitch which was referred to as a "fadeaway", often dominating batters for long periods of time with the pitch. However, Mathewson was certainly not a one-pitch pitcher, as he also had an excellent fastball and changeup, or "slowball" as it was called in Christy's time. While known as a gentleman in a game which at the time was not renowned for its class and style, Mathewson had a great deal of difficulty handling defeat early in his career, sometimes found to be sitting alone and crying after a particularly hard loss, and was considered by a team which was largely well-seasoned and battle hardened to be aloof and self-centered, especially early in his career. It was once said of him that, after a fan had mistaken another Giants player for Mathewson and asked his autograph, the player remarked, "It's a good thing that fella didn't ask Matty for his autograph; Matty would have told him to go fuck himself." Mathewson was allegedly even involved in a scuffle with a fan during one somewhat contentious game. (NY Times game account; to be posted)

While Mathewson was highly intelligent and articulate, and as such a man might seem to gravitate to those of like background, perhaps one of his best friends was a seldom-used backup catcher named Frank Bowerman, a player well-known for his dull intellect and quick temper. Mathewson and his manager, John McGraw, were also very close, and for a long period of time the Mathewsons and McGraws even shared an apartment.

During his illustrious 17-year career, Mathewson won 373 games, of which 79 were shutouts, while losing only 188 with an astonishingly low career ERA of 2.13. He had outstanding control, striking out 2,502 batters while walking only 844. He pitched in four World Series, his team winning it in 1905 when he won three games by shutout. In 1916 he was traded to the Cincinnati Reds, where he won the only game he pitched before becoming the team's manager.

His book Pitching in a Pinch (ghostwritten by John N. Wheeler) was published in 1912. It is an excellent picture of the baseball of that time, and includes an account of Fred Merkle's famous baserunning error.

During World War I, Christy Mathewson enlisted in the United States Army, serving overseas as a Captain in 1918. He died in Saranac Lake, New York at the age of 45, on the opening day of the 1925 World Series, after suffering from tuberculosis, which was widely considered to be a complication of being exposed to mustard gas during a training exercise. He is buried at Lewisburg Cemetery in Lewisburg, Pennsylvania.

His nickname was "Big Six", a reference to a famous New York fire engine of the time, though it also may have been short for "Big six footer", as Mathewson was considerably more stout than many players of his era. Also at times referred to as "The Christian Gentleman", Mathewson was said to have promised his mother that he would never pitch on Sunday, a promise he managed to keep. Mathewson was raised in a fairly stern Presbyterian home, and was well versed in Scripture.

In 1936, he became one of the first five players admitted to the Baseball Hall of Fame, along with Babe Ruth, Walter Johnson, Ty Cobb and Honus Wagner.

In 1999, he ranked number 7 on The Sporting News' list of the 100 Greatest Baseball Players, the highest-ranking National League pitcher. Later that year, he was elected to the Major League Baseball All-Century Team.

Christy Mathewson Day is celebrated as a holiday in his hometown of Factoryville, Pennsylvania, on the Saturday closest to his birthday.