He was taken to a hospital, where he was pronounced dead, an NYPD official told HuffPost.
No arrests have been made.
In 2008, Cali was arrested and charged with federal racketeering as part of Operation Old Bridge - a code name for the February 7 arrests in Italy and the US that targeted the Gambino crime family.
Infamous mob boss Francesco "Franky Boy" Cali has died.
Authorities believe Cali, who has kept a low profile in comparison to his predecessors, had ties to the Inzerillo mafia family in Sicily.
The last mob boss to be killed was Paul Castellano, also the leader of the Gambino crime family at the time, who was murdered outside Sparks Steakhouse in Midtown Manhattan in 1985.
Cali was the first NY crime family boss shot since 1985, when Paul Castellano, who owned a mansion on Todt Hill, was executed as he arrived at Sparks Steakhouse in Manhattan.
Francesco Cali, 53, was found with multiple gunshot wounds to his body outside his home on Staten Island, according to the New York Police Department.
It was a marked change from the Gotti era, which brought with its unnecessary attention and exposure.
NY media say it is the first targeted killing of a mob boss in the city since 1985.
According to local media, Cali ascended through the ranks, becoming a powerful capo of organised crime before turning 40 - less than 10 years after becoming an inducted member.
The Gambino criminal organisation is one of the "Five Families" of organised crime in NY, alongside the Bonanno, Colombo, Genovese and Lucchese families.
Prosecutors claimed that Cali was the Gambinos' ambassador to the Sicilian mobsters and the go-between for the two organisations.
The New York Daily News reported in 2008 that Cali was among 62 people arrested on federal racketeering charges and he later pleaded guilty to conspiring to extort money.