In an unnamed American city, soon-to-be-retiring detective William Somerset is partnered with short-tempered but idealistic David Mills, who recently transferred to the department, moving to the city with his wife Tracy. Mills introduces Somerset to Tracy, after which Somerset becomes her confidant. Tracy is unhappy with the city and feels it is no place to raise a child. She discloses to Somerset that she is pregnant and has yet to inform her husband. Somerset sympathizes with her, having a similar situation with his ex-girlfriend many years earlier, and advises her to tell Mills only if she plans on keeping the child.
Somerset and Mills investigate a pair of murders. The first victim is an obese man forced to eat until his stomach ruptured. The second was a wealthy defense attorney who died from both fatal bloodletting and the removal of a pound of flesh. At each crime scene, the murderer leaves behind clues for the detectives, including a single word: gluttony at the obese man’s home and greed at the attorney’s office. Somerset recognizes them as part of the seven deadly sins and realizes the murders are related. Other clues lead them to a possible perpetrator’s apartment. There, they find another victim, a known drug dealer and child molester, strapped to a bed, barely alive and emaciated, with a series of pictures indicating he had been tied to the bed for an entire year. The word sloth is scrawled on the wall. The photos also indicate the killer has been planning these deaths for some time.
Somerset and Mills identify a man named John Doe, who has checked out several library books on the deadly sins. Doe flees when they go to his apartment, and Mills gives chase. Doe eventually corners Mills and holds him at gunpoint, but after a few moments, turns and escapes. At Doe’s apartment, they find hundreds of handwritten journals showing Doe’s apparent psychopathy, and clues leading to a fourth victim. They arrive too late to prevent the death of the victim, a prostitute killed by an unwilling man forced by Doe to wear a bladed S&M phallic device on his genitals and to rape and kill her while severely traumatizing him. They find lust written on the door. They are alerted to their next victim, an attractive young woman, presumably a model, whose face has been mutilated by Doe; she was given the option to call for help and be disfigured, or to commit suicide by taking pills. She chose suicide. The word pride is written on her wall.