Born in Villalba, Province of Caltanissetta, Sicily, Bruno immigrated to the United States in his teens and settled in Philadelphia. The son of a grocer, Bruno was a close associate of New York Gambino crime family boss Carlo Gambino. Living with Bruno was a cousin of mobster John Simone. Bruno dropped the name Annaloro and replaced it with his paternal grandmother's maiden name, Bruno.
Bruno was married to Sue Maranca and had two children. Bruno owned an extermination company in Trenton, New Jersey, an aluminum products company in Hialeah, Florida, and a share in the Plaza Hotel in Havana, Cuba. Bruno's first arrest was in 1928 for reckless driving. Subsequent arrests included firearms violations, operating an illicit alcohol still, illegal gambling, and receiving stolen property.
In 1959, Bruno succeeded Joseph Ida as boss of the Philadelphia family. Over the next twenty years, Bruno successfully avoided the intense media and law enforcement scrutiny and outbursts of violence that plagued other crime families. Bruno himself avoided lengthy prison terms despite several arrests; his longest term was two years for refusing to testify before a grand jury. Bruno forbade family involvement in narcotics trafficking, preferring more traditional Cosa Nostra operations, such as bookmaking and loansharking. However, Bruno did permit other gangs to distribute heroin in Philadelphia for a share of the proceeds. This arrangement angered some family members who wanted a share of the drug-dealing profits.
Bruno preferred to operate through bribery rather than murder. For example, he banished violent soldier Nicodemo "Little Nicky" Scarfo to the then-backwater of Atlantic City for being too violent.
Later in his tenure, Bruno had to deal with the New York crime families' desire to operate in the increasingly lucrative Atlantic City gambling industry. The Five Families thought Atlantic City was far too lucrative for the Philadelphia family to get all of the action, although Atlantic City had long been regarded as Philadelphia's turf.
Several factions within the Philadelphia family began conspiring to betray the aging Bruno. On March 21, 1980, the 69-year-old Bruno was killed by a shotgun blast in the back of the head as he sat in his car in front of his home at the intersection of 10th Street and Snyder Avenue in South Philadelphia. It is believed that the killing was ordered by Antonio Caponigro (aka Tony Bananas), Bruno's consigliere. A few weeks later, Caponigro's body was found stuffed in a body bag in the trunk of a car in New York City. About $300 in bills were jammed in his mouth and anus (to be interpreted as signs of greed). The Commission had reportedly ordered Caponigro's murder because he assassinated Bruno without their sanction. Other Philadelphia family members involved in Bruno's murder were tortured and killed.
After Caponigro's murder, Philip "Chicken Man" Testa led the family for one year until he was killed by a nail bomb at his home. Testa's death resulted from an attempt by Peter Casella, Testa's underboss, and Frank "Chickie" Narducci, a capo, to become the Philadelphia boss and underboss. After Testa's death, Scarfo took over the Philadelphia family. In the ensuing years, the Philadelphia family would be decimated by government informants, more infighting, and the prosecutions of Scarfo and other mobsters.
In February 2016, author and historian Celeste Morello began an effort to designate Bruno's home a historical landmark. In March 2016, a historical landmark advisory committee ruled against the request.
Bruno is portrayed by actor Chazz Palminteri in the 2015 film Legend.