Canzoneri won his first title, the World Featherweight title, with a 15-round decision over Benny Bass on February 10, 1928. He defended the title once and then went up in weight and challenged World Lightweight Champion Sammy Mandell, losing by a decision in ten rounds. In 1930, Mandell was knocked out in the first round by Al Singer and lost his title and Canzoneri, who had already beaten Singer by a ten-round decision before, challenged Singer for the title on November 14, 1930, knocking him out in the first round to become a two division world champion. In defeat, Singer made history by becoming the first man, and only man up until John Mugabi, to both win and lose the title by knockout in the first round.

Canzoneri’s first defense was a unification of sorts: He faced World Light Welterweight champion Jack Kid Berg, who was putting his title on the line and trying to take Canzoneri’s lightweight crown. Canzoneri became a three-division world champion by knocking Berg out in the third round on April 24, 1931. Canzoneri, Barney Ross and Henry Armstrong were the only boxing champions in history allowed to hold two or more world titles simultaneously. (Sugar Ray Leonard became both the vacant World Super Middleweight and the World Light Heavyweight Champion in one night in 1988, but he could keep only one and chose to keep the Super Middleweight title.)

On May 10, 1935, he fought for the world lightweight title against Lou Ambers. Canzoneri won the World Lightweight title by outpointing Ambers over 15 rounds. After successfully defending his Lightweight title once, he lost it again in a rematch with Ambers by a 15-round decision. There was a rubber match between the two and Ambers once again won a decision in 15 rounds.