Firpo moved to the United States in 1922 after having compiled an outstanding record during the first three years of his career in South America. He won his first 10 American matches by knockout before being involved in a 10-round no-decision match against Homer Smith.

Firpo's slugging prowess earned him a September 14, 1923, heavyweight world title match with Jack Dempsey, (Dempsey, Jack) the reigning champion. Dempsey won this fight on a sensational second-round knockout, but in the first round a powerful punch delivered by Firpo knocked Dempsey completely out of the ring—a moment captured by the artist George Bellows (Bellows, George Wesley) in the painting entitled Dempsey vs. Firpo. Firpo continued boxing until 1936, but the match with Dempsey was his only world title bout. He had 36 recorded bouts, of which he won 29 (25 by knockout).