Based on the true-life book of lawman Burton Turkus, this movie chronicles the rise and fall of the organized crime syndicate known as Murder, Incorporated. Focusing on powerful boss Lepke and violent hitman Reles.

Abe Reles and his accomplice, Bug Workman, two cold-blooded killers from Brooklyn's Brownsville district, go to the Garment District to meet with Louis "Lepke" Buchalter, the smooth kingpin of an organized crime syndicate, who offers them a job as the syndicate's hit men. After hiring them to kill Walter Sage, a Catskill resort owner who has been withholding slot machine profits from the syndicate, Lepke designates Mendy Weiss, his right hand man, as Reles' contact. To get close to Sage, Reles enlists the help of down-and-out singer Joey Collins, an old crony of Sage, who owes Reles money. Coerced by Reles' veiled threats, Joey agrees to accompany Reles to the Catskills, where he draws an unsuspecting Sage out into the street and into Reles' murderous hands. Upon returning to the city, Reles visits Joey at the apartment he shares with his dancer wife Eadie and coldly announces that he will kill them both it they tell anyone about the murder. Aghast, Eadie denounces Reles and throws him out. Later, at a soda shop owned by the portly Rose Gorsi, Lt. William Tobin, a police officer determined to put an end to the reign of terror being waged by the syndicate, arrests Reles and takes him to the station house for questioning. When they arrive, however, Lazlo, Lepke's attorney, is already there with an order for Reles' release. Seething with resentment toward Eadie, Reles returns to the apartment when Joey is gone and brutally rapes her. When Joey returns home, the beaten and disheveled Eadie begs him to run away with her. When he refuses out of fear, Eadie becomes outraged and hysterically insists that he leave. Under Lepke's direction, Reles continues his murderous campaign. One day, he appears at the nightclub in which Eadie performs to ask her to reconcile with Joey. Inviting Eadie to meet with Joey, Reles takes her to a luxurious apartment filled with stolen goods and offers it to her and Joey for free. Soon after, when a grand jury impaneled by special prosecutor Thomas Dewey convenes, Lepke decides to hide out from the police at Joey and Eadie's apartment. Once there, Lepke takes control, treating Eadie like a maid and constantly issuing orders to her. Fearful that Joe Rosen, a shop owner he had beaten for failing to pay extortion money, will be called to testify against him, Lepke instructs Mendy to personally kill Rosen. As the New York police department scours the city for Lepke, Albert Anastasia, one of the crime lords, visits Lepke and informs him that the syndicate has voted that he must turn himself in on a reduced charge of interstate commerce crime. Lepke reluctantly consents, but rather than the two-year prison term promised by Albert, is sentenced to thirty years in Leavenworth. After District Attorney Burton Turkus takes over the crusade against Murder, Inc., he enlists Tobin's help in identifying the players. At first cynical about Turkus' ability to withstand political pressure, Tobin eventually agrees to join forces with the district attorney. Lepke, concerned that he can be linked to the Rosen murder, instructs Mendy to put out a contract on the entire Brownsville gang as well as Joey and Eadie. Shell-shocked from her time spent under Lepke's domination, Eadie visits Turkus to recount her life with the killers. Turkus listens in disbelief as she identifies Mendy as Lepke's right-hand man and discloses that the Brownsville Gang served as Lepke's personal killers. After Eadie informs Turkus that Reles is arriving that afternoon on the Baltimore train, Turkus puts her in protective custody and goes to the train station to arrest Reles. Later, as Mendy waits menacingly outside the soda shop to kill Joey, Turkus pulls up and hauls Joey into the police station, shows him photographs of Bugs's murder and warns that he will be next. Upon learning that Reles is in custody, Joey asks to see him. In Reles' cell, Joey announces that Bugs has been killed and then threatens to testify against Reles. Fearing that Joey will incriminate him for murder, Reles agrees to testify against Lepke in exchange for a reduced charge of second degree murder. Over the next six days, Reles furnishes a detailed account of the activities of Murder, Inc., including the fact that Joey overheard Lepke order Rosen's murder. Realizing that Joey's testimony could bring Lepke down, Turkus decides to put Joey and Reles in protective custody and hide them at the Half Moon Hotel in Coney Island. Eadie comes there to beg Joey to cooperate, but Joey, afraid of gang land retaliation against his wife, refuses. In tears, Eadie slips out of the hotel, leaving her guards behind, to stroll along a darkened pier, unaware that she is being followed. Suddenly a man springs from the shadows and strangles her. Later that night, as Reles sleeps, an assassin sneaks into his room and tosses him out the window, then drapes a sheet from the window to make it look like Reles died while trying to escape. Just as Turkus' crusade seems lost, Joey decides to rectify his wife's death by testifying against Lepke, who then is finally made to pay for his crimes in the electric chair.