Bensonhurst, Brooklyn 1972. John Barelli, a collection agent for local bookmakers, enters Francesi's Salumeria, where Nicky Morello works as a stock boy. Barelli has come to collect the past due debt of the storeowner's son, a degenerate gambler. Barelli drags the aging proprietor out into the street and begins to beat him. A crowd of midday shoppers surrounds them as the elevated B train roars by above. When no one comes to the old man's defense, twelve-year-old Nicky leaps on to Barelli's back. The boy's small hands find purchase in the gangster's eye sockets and Nicky immediately realizes the futility of his situation. Suddenly Barelli howls in pain and, as he does a pair of strong arms lift Nicky beyond the perimeter of the crowd. As the old man lies near death against the curb, the bleeding gangster offers a c-note to anyone in the crowd willing to identify the kid who bit off his ear. No one responds. The sound of screeching rubber follows Barelli's fishtailing cherry red Caddie Eldorado convertible down the street, leaving in its wake an acrid cloud of smoke to settle on the scene of his depravity.
Thirty-five years later Professor Niccolo Morello lectures a class on the papacy of Alexander VI, the last Borgia Pope. The class enjoys the wisecracking, street-smart perspective their bespectacled teacher brings to the subject. Morello explains how the Pope appoints his two illegitimate sons Cesare and Juan cardinals and then goes on to defile his daughter Lucretzia, who produces a third son, the Infans Romanus. One morning Juan's body is found floating in the Tiber, stabbed to death by his brother Cesare, historians believe, over a jealous rage for their sister's affection.
The lecture is the allegorical source of Killing John Barelli, a mystery narrated by Nick Morello a widowed father, who months before his marriage to Nora Waites, stumbles upon a dark secret: Nora was raped as a child by her father, Henry, then the Governor of Connecticut. The Waites' family's more public tragedy is the suicide of Nora's older brother Johnny that occurred weeks later, at the family compound in New Britain. Nick discovers the Governor is being blackmailed by John Barelli; now the mastermind of a church in Spanish Harlem that launders his ill-gotten cash. Among the church's parishioners is Nora's misanthropic brother, Roy, who Nora believes murdered their brother Johnny. Barelli has his sights set on the Waites School for Emotionally Challenged Children, which sits atop some very valuable Manhattan real estate. Other than Nick, the school is Nora's greatest love. Nick becomes conflicted as he begins to behave more and more like his adversaries. Is he the man Nora fell in love with or the boy from Brooklyn, who bit off a gangster's ear? From the mean streets of Nick's old Bensonhurst neighborhood to his life on New York's elite Upper Eastside to a fifteenth century palazzo in Venice; inside the classroom and out, the reader is treated to lessons in renaissance history and Nick Morello's brand of Machiavellian street justice as he takes on those, who would harm the woman he loves.