Bithorn played for the San Juan Senators and at age 22 became the youngest manager in the history of Puerto Rican winter ball. Soon enough, he was pitching at Wrigley Field.

On April 15 of 1942, Bithorn made history when he pitched for the first time for the Chicago Cubs in the National League. Bithorn won nine games and lost fourteen in his first season, but he rebounded in 1943 by going 18-12 and completing 19 of his 30 starts, and leading the league in shutouts with seven, establishing a record for Puerto Rican pitchers that still stands.

Bithorn fought for the United States military in World War II. His promising start, though, did not last once he returned from military service. After going 6-5 in 1946 for the Cubs, he moved across town to the White Sox and only pitched two innings in 1947, developing a sore arm that ended his career.

In four seasons, Bithorn had a 34-31 record with 185 strikeouts, a 3.16 ERA, 30 complete games, eight shutouts, five saves, and 509 innings pitched in 105 games (53 as a starter).

Bithorn tried a comeback a few years later in the Mexican winter league. But on New Year's Eve 1952, at age 35, he was shot to death by a policeman in Mexico. Reports on the shooting were sketchy, and the circumstances have always been a mystery.

Bithorn's achievement of making it to the majors remained a source of pride in Puerto Rico, and he was honored in 1962 when the biggest ballpark on the island was built and named for him. Hiram Bithorn Stadium is located next to Roberto Clemente Coliseum and across the street from Plaza Las Américas, and it also has hosted world championship boxing fights, the 1979 Pan American Games, and important musical spectacles. The Montreal Expos played 22 home games there in both 2003 and 2004. Rounds 1 and 2 of the 2006 World Baseball Classic were played here including teams from Group C and Group D.