Ten years after tracking down serial killer Jame Gumb, FBI Special Agent Clarice Starling (Moore) is unjustly blamed for a bungled drug raid. Starling and her connection to Hannibal Lecter (Hopkins) come to the attention of Lecter's only surviving victim, Mason Verger (Gary Oldman), a wealthy child molester whom Lecter left paralyzed and horribly disfigured during a therapy session.
In an unnamed American city, soon-to-be-retiring Detective William R. Somerset (Freeman) is partnered with short-tempered-but-idealistic Detective David Mills (Pitt), who recently transferred to the department. Together, their first case leads them to believe that they are chasing a serial killer whose killings each reflect one of the seven deadly sins. First, they discover an obese man who was tied to a chair and forced to eat food, and eventually, his own vomit, until his stomach exploded (representing gluttony). Next, they investigate the fatal bloodletting of a rich attorney, from whom a pound of flesh has been extracted (representing greed). Two days later, fingerprints left at the crime scenes lead them to an apartment, where they find an emaciated man strapped to a bed. Though he initially appears to be dead, they find he has been kept alive and immobile by the killer for one year to that day; a drug dealer and child molester before his capture (representing sloth). Though unable to learn anything from the insensate man, the detectives agree the killer has planned these crimes for more than a year.
Clarice Starling (Jodie Foster) is pulled from her training at the FBI Academy at Quantico, Virginia by Jack Crawford (Scott Glenn) of the Bureau's Behavioral Science Unit. He assigns her to interview Hannibal Lecter, a former psychiatrist and incarcerated cannibalistic serial killer, whose insight might prove useful in the pursuit of a serial killer nicknamed "Buffalo Bill", who skins his female victims' corpses.
In Stockholm, Sweden, journalist Mikael Blomkvist, co-owner of Millennium magazine, has lost a libel case brought against him by businessman Hans-Erik Wennerström. Lisbeth Salander, a brilliant but troubled investigator and hacker, compiles an extensive background check on Blomkvist for business magnate Henrik Vanger, who has a special task for him. In exchange for the promise of damning information about Wennerström, Blomkvist agrees to investigate the disappearance and assumed murder of Henrik's grandniece, Harriet, 40 years ago. After moving to the Vanger family's compound, Blomkvist uncovers a notebook containing a list of names and numbers that no one has been able to decipher.
In Baltimore, Maryland psychiatrist Dr. Hannibal Lecter attends a symphonic orchestra performance of A Midsummer Night's Dream. The flute player repeatedly misses out on his part, profoundly irritating Lecter. Later, Lecter hosts a dinner party in his townhouse for the orchestra's board of directors at which the disappearance of a musician, a flute player, is brought up during conversation.
Scientist Sebastian Caine has developed a serum that can make a subject invisible. His team of scientists, which includes ex-girlfriend Dr. Linda McKay and Dr. Matt Kensington, eventually enable the serum to work on a gorilla and restore it to visibility. Sebastian once again becomes obsessed with Linda while unbeknownst to him, she has become involved with Matt. Instead of reporting his success to the military, Sebastian lies to the oversight committee, which includes his mentor Dr. Howard Kramer, convincing his team to go right into human testing. The procedure is performed on Sebastian. It is successful and Sebastian turns completely invisible. He then enjoys sneaking around the lab in order to scare and play pranks on his fellow co-workers. They become worried that he is taking it too far. After three days, he is unable to revert to visibility.
College student Nick O'Bannon watches a race at McKinley Speedway for a study break with his girlfriend Lori Milligan, and their friends Janet Cunningham and Hunt Wynorski. While watching the race, Nick has a premonition that a race car crash will send debris into the stands, causing the stadium to collapse, and killing numerous people. When Nick panics, a fight breaks out, and several people leave before Nick's vision becomes a reality including Lori, Janet, Hunt; security guard George Lanter; mechanic Andy Kewzer; mother Samantha Lane; tow truck driver Carter Daniels; and Andy's girlfriend Nadia Monroy. Nadia gets angry and yells at them when she is suddenly obliterated by a stray tire that flies out of the stadium.
Set twenty-five years after Child's Play, the Chucky doll (voiced by Brad Dourif) mysteriously arrives in the mail of the home of paraplegic Nica Pierce (Fiona Dourif) and her mother, Sarah. Later that night Sarah is found dead from a stab wound and her death proclaimed a suicide.
High school student Casey Becker receives a flirtatious phone call from an unknown person, asking her, "What's your favorite scary movie?" The situation quickly escalates as the caller turns sadistic and threatens her life. He reveals that her boyfriend Steve Orth is being held hostage. After Casey fails to answer a question correctly about horror films, Steve is murdered. When Casey refuses to cooperate with the caller, she is attacked and murdered by a masked killer. Her parents come home to find her body hanging from a tree.
While attending a preview of the film Stab, a film within a film based on the Woodsboro murders depicted in Scream, two Ohio Windsor College seniors, Maureen Evans and Phil Stevens are murdered by Ghostface. Phil is stabbed through the ear in a bathroom stall while trying to eavesdrop on strange whimpering noises. The killer, wearing a Ghostface costume, then returns to the screening and sits beside Maureen, before mortally stabbing her. At first the audience believe she is part of the raucuous acting out by audience members, until she falls dead in front of the cinema screen.
In West Texas, 1980, Ed Tom Bell laments the increasing violence in a region where, like his father and grandfather before him, he has become sheriff. Anton Chigurh, a hitman, strangles a sheriff's deputy to escape custody and steals a car by using a captive bolt pistol to kill the driver.
After Amanda Young seals him in the bathroom, Eric Matthews escapes his shackle by breaking his foot with a toilet tank cover. Six months later, he is still missing. A SWAT team led by Lieutenant Daniel Rigg discovers the site of a Jigsaw game in which the victim, Troy, had to escape a bomb by ripping chains from his body. Rigg calls Detectives Mark Hoffman and Allison Kerry, who is guilt-ridden over Matthews' disappearance, to the scene. Kerry points out that the door was welded shut, breaking Jigsaw's modus operandi of giving his victims a chance to escape. She is abducted from her home that night while reviewing Troy's tape and awakens in a harness that is hooked into her ribs. She manages to retrieve the key from a suspended beaker of acid and unlocking it before the timer expires, but it tears her rib cage apart anyway, killing her.
Cotton Weary, now living in Los Angeles and the host of a nationally syndicated television show, 100% Cotton, is called by Ghostface, who demands the whereabouts of Sidney Prescott, who has gone into hiding ever since the events of the second film. Cotton refuses to divulge that information, and when Ghostface comes to his home, both Cotton and his girlfriend Christine are murdered.
The Salesman steps out of the elevator and walks onto a penthouse balcony where The Customer, wearing a beautiful red dress, looks out over Basin City. He offers her a cigarette and says that she looks like someone who is tired of running and that he will save her. She smiles to him, the two share a kiss and he shoots her; she dies in his arms. He says he will never know what she was running from but that he’ll cash her check in the morning.