The opening sequence takes the form of a computer simulation run by Satan to analyze souls and determine individual weaknesses to exploit and corrupt. The program finally settles on Elliot Richards (Brendan Fraser), a geeky, over-zealous man working a dead-end technical support job in a San Francisco computer company. He has no friends and his co-workers are always avoiding him. He has a crush on his colleague, Alison Gardner (Frances O'Connor), but lacks the courage to ask her out. After Elliot is again ditched by his co-workers at a bar while trying to talk to Alison, he says to himself that he would give anything for Alison to be with him. Satan, in the form of a beautiful woman (Elizabeth Hurley), overhears him and offers to give Elliot seven wishes in return for his soul.
The film opens in a 2010 firefight in a palm grove in the Diyala Province of Iraq. Three Marines discover an underground cavern and start to scream as their helmet video feed goes black. In The Bronx in 2013, NYPD officer Ralph Sarchie (Eric Bana) stands over the corpse of an infant in a darkened alley. He and his partner Butler (Joel McHale) resume their nocturnal patrol for the 46th Precinct. A domestic disturbance call comes in over the radio. Sarchie probes the dispatcher for more information and finds out that the male at the address is a former Marine. He tells Butler that his "radar" is going off because maybe the former Marine still thinks he is fighting in the war.
Al Simmons (Michael Jai White) is a special forces agent and black ops soldier. Jason Wynn (Martin Sheen), head of the covert government agency for which Simmons works, assigns him to infiltrate a biochemical weapons plant in North Korea. Unbeknownst to Simmons, Wynn has ordered his top assassin, Jessica Priest (Melinda Clarke), to murder him while he is on his mission. After Simmons dies in a gas fire, he arrives in Hell, where the demon king Malebolgia (Frank Welker), offers him a Faustian deal: if Simmons becomes his eternal servant and leader of his army in Armageddon, he will be able to return to Earth to see his fiancée, Wanda Blake. Simmons accepts the offer and returns to Earth.
George and Kathy Lutz are a young married couple who have recently purchased a home and move into the property. George appears not to be strong of faith, but Kathy is at least a nominal Catholic. The couple turn to Father Delaney to bless the home, but Delaney encounters troubles in trying to bless the home, including a room full of flies, out of season; violent stomach sickness; and later, blisters on his palm when trying to make a phone call to Kathy at their home.
A newly separated couple Clyde (Jeffrey Dean Morgan) and Stephanie Brenek (Kyra Sedgwick) live in different homes. After Clyde picks up their two children, Emily "Em" (Natasha Calis) and Hannah (Madison Davenport), for the weekend, they stop at a yard sale where Em becomes intrigued by an old wooden box that has Hebrew letters engraved on it. Clyde buys the box for Em, and they later find that there seems no way to open it. That night, Em hears whispering coming from the box. She is able to open it, and finds a tooth, a dead moth, a wooden figurine, and a ring, which she begins to wear. Em becomes solitary, and her behavior becomes increasingly sinister; she stabs her father in the hand with a fork. The house becomes infested with moths.
The film opens with a scene left off from Paranormal Activity 3 where Katie and Kristi are watching Dennis getting his spine crushed by a mysterious force. Grandma Lois takes the girls upstairs while an unseen force takes the camera with them. They all go into a dark room while a man encounters the girls and talks to them about "Toby" and how they are critically important to his plan.
The film opens with a bloodied and terrified priest slowly making his way across the bodies of thousands of dead soldiers. There are many crows and hyenas roving around the bodies. The priest reaches the dead body of another priest and tries take a small demon idol of the head of Pazuzu from his hand, but, suddenly, the dead priest briefly comes back to life and stops the living priest from taking it. The camera pulls back to reveal that the entire valley is littered with dead soldiers, many have been crucified upside down. The movie then cuts to Cairo, Egypt in 1949, where the young Father Lancaster Merrin (played by Skarsgård, who played the same part in Dominion: Prequel to the Exorcist) has taken a sabbatical from the Church and devoted himself to history and archaeology as he struggles with his shattered faith. He is haunted especially by an incident in a small village in the occupied Netherlands during World War II, where he served as parish priest: near the end of the war, a sadistic Nazi SS commander, in retaliation for the murder of a German trooper, forces Merrin to participate in arbitrary executions in order to save a full village from slaughter.
Barbara and Adam Maitland decide to spend their vacation decorating their idyllic Connecticut country home. As the two are driving home from a trip to town, Barbara swerves to avoid a dog and the car plunges into a river. After they return home, she and Adam notice that they now lack reflections and they discover a Handbook for the Recently Deceased.
A security guard is running through a subway station, he eventually enters a room he cannot escape from and starts begging his reflection in a mirror for his life. Suddenly, his reflection cuts its throat with a mirror shard, killing the "real" security guard.
The Reverend Cotton Marcus (Patrick Fabian) lives in Baton Rouge, Louisiana with his wife and son. Marcus, who lost his faith after the birth of his ill son, is accustomed to performing fake exorcisms on "possessed" individuals. He chooses an exorcism request sent by farmer Louis Sweetzer (Louis Herthum), who claims his livestock is being slaughtered by his daughter Nell (Ashley Bell) who is possessed.
Doctor Parnassus' (Plummer) theatre troupe, which includes sleight of hand expert Anton (Garfield), confidant Percy (Troyer), and Parnassus' daughter Valentina (Cole), performs outside a London pub. A drunk (Richard Riddell) barges onstage and crashes through a stage mirror, where his face changes (Bruce Crawford), and he enters a journey of imagination that culminates in a choice between a torturous-looking twelve-step program and going to a pub. He enters the pub, but it explodes; in the real world, Parnassus says he has lost another one to Mr. Nick (Waits).
Alexandra Medford (Cher), Jane Spofford (Susan Sarandon), and Sukie Ridgemont (Michelle Pfeiffer) are three dissatisfied women living in the picturesque town of Eastwick, Rhode Island. Alex is a sculptor and single mother of one daughter; Jane is a newly divorced music teacher unable to have children; while Sukie has six daughters and works as a columnist for the Eastwick Word. The three friends have all lost their husbands (Alex's died, Jane's divorced her, and Sukie's abandoned her). Unaware that they are witches, the women unwittingly form a coven where they have weekly get-togethers and share their fantasies about ideal men.
Katherine Winter (Hilary Swank) and colleague, Ben (Idris Elba), investigate and disprove claims of miracles. In Louisiana, Katherine receives a call from a friend, Father Michael Costigan (Stephen Rea), who says that his photographs of her have developed burn marks that when assembled, form a sickle-like symbol, a possible warning from God, which she ignores. She meets Doug Blackwell (David Morrissey), a teacher from the nearby town of Haven, who asks Katherine to find out why Haven's river has turned red. The locals believe this is a biblical plague caused by a girl, Loren McConnell (AnnaSophia Robb), who they believe killed her older brother in the river. They travel to Haven where Katherine meets Loren and has a vision of her turning the river red. Meanwhile, Ben witnesses dead frogs seemingly fall from the sky. Doug invites them to spend the night at his house, since the town doesn't have a motel. That night as they're about to eat dinner, they encounter flies and disease, which kills off local cows. Later that evening, Katherine explains to Doug at his wife's grave why she left the church; five years ago, she was an ordained minister. After a drought while doing missionary work in the Sudan with her husband and daughter, the locals sacrificed her family, believing they were the cause.
In Rome, American diplomat Robert Thorn (Gregory Peck) is in a hospital where his wife Katherine (Lee Remick) gives birth to a boy, whom he is told dies moments after being born. Robert is convinced by the hospital chaplain, Father Spiletto (Martin Benson), to secretly adopt an orphan whose mother died at the same time. Robert agrees, but does not reveal to his wife that the child is not theirs. They name the child Damien (Harvey Spencer Stephens).
Dean Corso (Johnny Depp), a New York City rare book dealer, makes his living conning people into selling him valuable antique books for a low price, and then selling them for profit. He meets with wealthy book collector Boris Balkan (Frank Langella), who has recently acquired a copy of The Nine Gates of the Kingdom of Shadows by 17th-century author Aristide Torchia, one of only three copies known to exist. According to legend, the book is Torchia's adaptation of an older book written by the Devil himself and purportedly contains the means to ritualistically summon the Devil and, through him, acquire invincibility and immortality. Balkan believes two of the copies are forgeries. He hires Corso to authenticate all three copies, and acquire the legitimate copy by any means necessary.