Born in Palermo, Sicily, Gambino is believed to have entered the U.S. illegally. A leading figure in the Gambino-Castellano faction within the D'Aquila-Mineo Mafia organization in Brooklyn and the Bronx, Gambino sided with Salvatore Maranzano in the Castellammarese War.
In the 1950s, following Albert Anastasia's rise to command, Gambino was named underboss of the crime family. He was tentatively supported as boss following the murder of Anastasia. Anastasia loyalists continued to resist him. One leader of that cause, Armand Thomas Rava, disappeared. Gambino eventually appointed another, Aniello Dellacroce, as his underboss.
Gambino died of a heart attack at his home on Long Island in 1976.