In 1917, Firpo began his professional boxing career by beating Frank Hagney by a decision in six in Buenos Aires. Originally declared a no decision, the bout's result was later changed to a win for Firpo.
For his second bout, he travelled, on January 1918, to Montevideo, Uruguay, where he suffered his first defeat, a first round knockout at the hands of Angel Rodriguez. He put a string of six wins in a row after that, and so on November 1 of 1919, he found himself challenging Dave Mills in Santiago, for the South American Heavyweight title. He lost on that occasion by a decision in 15 rounds, but then came back with a win over Andres Balsa by a knockout in round six.
On April 20 of 1920, he and Mills had a rematch and Firpo won the title with a first round knockout. After one more win, he and Mills faced each other in a rubber match, and the result was the same as that of their second bout: Firpo the winner by a knockout in the first. In 1921, Firpo had a raise in quality of opposition, when he defeated fringe contender Gumboat Smith twice, the first by decision in 12 and the second by knockout, also in 12.
In 1922, he continued his raise in the Heavyweight rankings by winning all four of his fights by a knockout.
Firpo began 1923 by knocking out former title challenger Bill Brennan in the 12th round. He followed that with seven more wins in a row, including wins over Jack McAuliffe and former world champion Jess Willard. After a win against Charlie Weinert, Firpo challenged world Heavyweight champion Jack Dempsey, at New York on September 14. Firpo became the first hispanic in history to challenge for the world's Heavyweight championship when he met Dempsey. Firpo was floored seven times before he trapped Dempsey against the ropes and launched a combination that sent Dempsey out of the ring in round one. Dempsey hit his head against a writer's typing machine, and for one moment, it looked as if Firpo would become the first hispanic in history to become world Heavyweight champion. But Dempsey got up at the count of nine, and proceeded to knock Firpo out in round two. This fight has been called by critics and experts as one of the greatest fights in history. Despite losing, Firpo gained substancial fame all over Latin America after this bout, as many people on different parts of that region spoke about his feat of dropping Dempsey.
In 1924, Firpo won his first three fights by knockout, but then lost his last two by decision, the last of which was to legendary Black challenger Harry Wills.
He retired for a short period, but came back in 1926 to beat Erminio Spalla by a decision in ten. Then, he kept away from the fight game for nine years, but he attempted another comeback in 1936, winning two fights before being beaten by a knockout in three by future Joe Louis challenger Arturo Godoy.
Firpo's popularity around Latin America could not be measured until years later, when a professional football team in El Salvador, a Latin American country that is thousands of miles away from Firpo's Argentina, was named after him. In addition, various schools, streets and avenues across Latin America have been named after him.
Firpo had a record of 32 wins and 6 losses in 38 fights, with 26 wins by knockout.