Giancana was born Gilormo Giangana on May 24, 1908,in The Patch neighborhood of Chicago to Antonio Giangana and Antonia DeSimmona, Italian immigrants from Castelvetrano, Sicily, Italy. His father immigrated in 1905, while his mother immigrated in 1906; he had seven siblings. Antonia died in 1910 and his father married Mary Leonardi. On September 23, 1933, Giancana married Angeline DeTolve, the daughter of immigrants from the Italian region of Basilicata. They had three daughters, Antoinette born 1935, Bonnie born 1938, and Francine born 1945. Angeline died on April 23, 1954, leaving him to raise his daughters.

Giancana joined the 42 Gang, a juvenile street crew working for political boss Joseph Esposito. (The 42 Gang’s name was a reference to Ali Baba and the 40 Thieves. They thought they were one better, hence 42) Giancana soon developed a reputation as an excellent getaway driver, a high earner, and a vicious killer. After Esposito’s murder, in which Giancana was allegedly involved, the 42 Gang was transformed into a de facto extension of the Chicago Outfit. The Outfit was initially wary of the 42ers, thinking them too wild. But Giancana’s reputation gained him the notice of Outfit leaders such as Frank “the Enforcer” Nitti, Paul “the Waiter” Ricca, and Tony “Joe Batters” Accardo. He was first arrested in 1925, for auto theft. He soon graduated to “triggerman”, and by the age of 20 had been the prime subject of three murder investigations, but never tried for any of them. In 1929, Giancana was convicted of burglary and larceny, and sentenced to one to five years in the Joliet Correctional Center. He was released in 1932, after serving three years and nine months.

During the late 1930s, Giancana became the first 42er to join the Chicago Outfit. From the early 1940s through the 1950s, he controlled most of the illegal gambling, illegal liquor distribution, and numerous other political rackets in Louisiana through longtime friend H. A. (Hol) Killian. Killian controlled the majority of the liquor license issuance by his associations with longtime New Orleans business associate Carlos Marcello. In 1939 Giancana was convicted of bootlegging, and sentenced to four years in Leavenworth Prison and Terre Haute Federal Correctional Complex.