Gambino was born in Palermo, Sicily, Italy, on August 24, 1902,[nb 1] to a family that belonged to a Sicilian Mafia gang from Passo di Rigano. He had two brothers, Gaspare Gambino, who was not involved with the Mafia, and Paolo Gambino who was a part of the Gambino crime family. His parents were Italian immigrants Tommaso Gambino and Felice Castellano.
Gambino entered the United States on December 23, 1921, at Norfolk, Virginia, as a stowaway on the SS Vincenzo Florio. He then joined his cousins, the Castellanos, in New York City. He had worked for a small trucking firm owned by his uncle's family.
Gambino later moved to a modest house located at 2230 Ocean Parkway in Brooklyn; his Long Island residence, located at 34 Club Drive in Massapequa, served as his summer home. The two-story brick house, surrounded by a low fence with marble statues on the front lawn, was at the end of a cul-de-sac in Harbor Green Estates, overlooking the South Oyster Bay. In 1932, Gambino married one of his cousins, Catherine Castellano, sister of Paul Castellano. They raised four children – sons Thomas, Joseph (March 28, 1936 – February 20, 2020) and Carlo (born 1934), and a daughter, Phyllis Gambino Sinatra (September 22, 1927 – February 19, 2007).

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