In an unidentified city of constant rain and urban decay, Detective William Somerset is preparing to retire and leave the horrors of the city. Before he does he is partnered with Detective David Mills, a cocky, young and short-tempered cop from a small town. The two investigate the murder of a highly obese man who was fed spaghetti until his stomach burst from a kick. Somerset investigates the murder while Mills is given the murder case of Defense Attorney Eli Gould, with GREED written in Gould's blood on the floor. Soon after, Somerset finds GLUTTONY written behind the obese man's fridge and theorizes that a serial killer is basing his crimes on the Seven Deadly Sins, with five more to go.

To give Mills and Somerset a chance to get along, Mills' wife, Tracy (Gwyneth Paltrow) invites Somerset over for dinner. After Tracy goes to bed, Mills and Somerset examine case evidence from the two scenes. They find a picture of Gould's wife with blood painted around the eyes. The Detectives have a distraught Mrs. Gould look at the pictures in a safe house and she notices an abstract painting that is upside down. Brushing powder on the wall behind the painting, Somerset finds fingerprints outlining the words "Help Me."

After running the fingerprints through AFIS, the prints are traced a day later to a pedophile named Victor, who escaped conviction for the rape of a minor due to the efforts of his lawyer: Eli Gould, the GREED victim. SWAT and the detectives raid his apartment to find Victor to be the SLOTH victim, having been bound to his bed for a year exactly, as evidenced by pictures at the scene; one taken every day from the day he is discovered. Remarkably, he is still alive but suffering from severe physical and mental deterioration. His hand was cut off to leave the prints. After asking to interrogate Victor in the hospital, the doctor says that his "brain is mush" and that his death is imminent anyway.

That evening, Tracy calls Somerset and requests that he meet with her. The next morning, Somerset meets Tracy in a diner where she tells him how miserable she is in "the city". At Somerset's urging, Tracy reveals the truth of her request to meet: she is pregnant, afraid of raising a child where they now live and afraid of telling her husband, David.

Later that day, and using a contact in the FBI, Somerset gets a library list of people who have borrowed books related to the Seven Deadly Sins. The list leads the detectives to a man named John Doe, whose apartment they visit soon after. Doe, his face hidden, sees them as he comes home and pulls out a gun. After a long chase, Doe hits Mills with a tire iron, keeps him subdued at gunpoint, but lets him live and suddenly flees. While examining Doe's apartment (after bribing a resident to claim she called the detectives about Doe) they find notebooks of his thoughts, trophies of the crimes and a picture of Mills fighting off Doe, who, at the time, was posing as a press photographer. They also find