There is evidence to suggest that Cascio-Ferro spent some of his younger years in New York and New Orleans before returning home as an important Mafioso in Sicily. He kept in close touch with Mafiosi in both American cities through the 1900s and apparently worked with the transplanted criminals on a counterfeiting racket. Sources indicate a number of visits by Cascio-Ferro to those cities. When in New York, he reportedly stayed with members of the Lupo-Morello Mob. During the visits, he is credited with helping American mobsters refine their practices for extorting protection money from businesses. Cascio-Ferro showed the gangs they could maximize profits by extorting sums that were not financially damaging to the businesses - a practice called "wetting the beak."

He is thought to have organized (with Lupo, deported Sicilian-American Mafiosi and some New Orleans hit men) the assassination of gangbuster Lt. Joseph Petrosino of the New York Police during Petrosino's official visit to Sicily in 1909. Legend says Cascio-Ferro excused himself from a dinner party at the home of a Sicilian government official, borrowed his host's vehicle and went to deliver the coup de grace shot to the head of Petrosino. Then, of course, he returned to complete his friendly visit with the official. Cascio-Ferro never denied involvement in the Petrosino murder.

At some point, he appears to have had a falling out with the Lupo-Morello organization, possibly over the counterfeiting racket, possibly over his plans to assume control of the American mob. In the 1910s and 20s, Cascio-Ferro was busy exporting select Mafiosi from Sicily to destinations in the U.S. A wave of Mafiosi, many of whom proved antagonistic to the Morello group, washed up on American shores, including Carlo Gambino, Salvatore Maranzano, Joe Bonanno, Joe Magliocco and Vincent Mangano. Some have suggested that Maranzano's purpose in organizing resistance against New York boss Joe Masseria, who emerged from the Morello gang, was preparation for the arrival of Cascio-Ferro himself.

But the Sicilian supreme boss would never make that final trip. In 1929, he went on trial - on probably trumped-up charges - just as the Castellamarese War was breaking out in the U.S. He was convicted and imprisoned, dying behind bars. The date of his death is generally given as 1945, but author Arrigo Petacco ("Joe Petrosino," 1974) found evidence of Cascio Ferro's demise in summer of 1943. Petacco says the Mafia leader was left behind in his cell when other inmates of Pozzuoli prison were evacuated in advance of the Allied invasion. The author says Cascio Ferro died of thirst.