Abe Reles (Falk) and Bug Workman (Warren Finnerty), two killers from Brooklyn's Brownsville district, meet in the Garment District to meet with Louis "Lepke" Buchalter, kingpin of an organized crime mob, who hires them as the syndicate's hit men.
Their first job is to kill Walter Sage, a Catskill resort owner who has been holding back slot machine profits from Lepke. To get close to Sage, Reles forces singer Joey Collins (Stuart Whitman), an old crony of Sage who owes Reles money, to help him. Reles and his henchman kill Sage. Reles visits Joey and threatens to kill him and his dancer wife Eadie (May Britt) if they tell anyone about the murder. Eadie throws Reles out. Reles later returns to the apartment when Joey is gone and brutally rapes her. Despite her urging Joey refuses to run away, and this causes him and Eadie to split up.
Reles continues to carry out assassinations at Lepke's direction. Reles reconciles with the couple by giving them a luxurious apartment filled with stolen goods. Under police pressure, Lepke hides out from the police at Joey and Eadie's new apartment. He treats Eadie like a maid.
District Attorney Burton Turkus (Henry Morgan) takes over the law enforcement campaign against Murder, Inc., enlisting local Brownsville police detective Tobin (Simon Oakland). Lepke orders the death of the entire Brownsville gang as well as Joey and Eadie. Eadie visits Turkus and becomes an informant, as does Joey. He then confronts Reles, who has been arrested, in his cell, and threatens to testify against him. In fear of that, Reles agrees to testify against Lepke in exchange for reduced charges. He provides a detailed account of the activities of Murder, Inc.
Turkus puts Joey and Reles in protective custody and hides them at the Half Moon Hotel in Coney Island. Eadie comes to visit Joey and is murdered nearby. Later that night, Reles is thrown out the window by an assassin. Joey avenges his wife's death by testifying against Lepke, who is executed.