Jerry Fletcher (Mel Gibson), an obsessivecompulsive New York City taxi driver, visits his friend Alice Sutton (Julia Roberts), who works for the U.S. Attorney, at the Justice Department. She is trying to solve her father's murder. Jerry tells her that NASA is trying to kill the President using a secret weapon on the Space Shuttle that can trigger earthquakes.
Jerry identifies some men on the street as CIA, follows them into a building, and is captured by them. He wakes up in a mental hospital bound to a wheelchair. A doctor (Patrick Stewart) tapes his eyes open, injects him with LSD, and interrogates him using torture. As the LSD kicks in Jerry remembers many previous sessions, which he sees as terrifying cartoons. In a fit of panic, Jerry manages to bite the doctor's nose and sufficiently incapacitate him long enough to escape, still bound to the wheelchair. He manages to shut himself in a laundry truck, escaping the premises. Jerry goes to Alice's office again and grabs a guard's gun, collapsing in Alice's arms.
Alice visits Jerry in the hospital. Handcuffed to the bed and forced to enter a drug-induced sleep, he pleads with her to switch his chart with that of a criminal in the next bed or he will be dead by morning. In the morning, when Alice visits again, the criminal is dead, as he has suffered a mysterious heart attack during the night. The CIA, FBI and other agencies are there. She meets a mysterious CIA psychiatrist, Dr. Jonas. Meanwhile Jerry fakes a heart attack and escapes again, dropping himself down a linen chute. Jerry dresses up as a doctor and escapes the building.
Jonas quizzes Alice over lunch; she explains that Jerry saved her from muggers once, so she tolerates him. In Jerry's hospital room she finds a copy of The Catcher in the Rye. As she discusses it with an FBI officer named Lowry, the CIA come and confiscate all of Jerry's personal items. Lowry offers to share information with her but she declines.
The CIA cannot find Jerry. Alice goes to her car, and finds Jerry hiding in it. She stops the car and speaks with Lowry, who is tailing them, and then they go to Jerry's apartment where he tells her about his conspiracy theories and his newsletter. He has dozens of copies of Catcher. He feels compelled to buy it, but doesn't know why. They are interrupted when Jerry's alarm goes off, signaling the entry of a CIA SWAT team. Jerry sets everything on fire and they leave by his secret trapdoor exit. In the room below, there is a large mural on the wall, which features both Alice and the triple smokestacks of a factory near the mental institution.
The pair go to Alice's apartment and he reveals he's been watching her through her window. She kicks him out. Outside, Jerry confronts Lowry and his partner staking out her place, and he warns them, at gunpoint, not to hurt her. He goes to a book store and buys a copy of Catcher. The CIA detects his purchase, and sends agents to catch him. Jerry sees their black helicopters with men rappelling down and goes into a theater. He yells "there's a bomb under my chair" and manages to escape during the resulting panic.
The next morning, Alice has been calling each person who gets the newsletter, and they have all died that night except one. Jerry uses a ruse to get her out of the office, and then attaches cables from the CIA vehicle following her to a vendor's cart. On a bus they discuss more of his theories. In a subway station where one Herriman drowned in another conspiracy, she agrees to check the autopsy. He says he loves her and she rejects him.
Alice goes to see the last surviving person on the subscription list, and it is Jonas. He explains that Jerry was an MK-ULTRA subject but the project was terminated - except for his research. Jonas shows her a photo of her father taken from Jerry's locker, and claims that Jerry went out of control and killed her father. She is crushed.
Jerry sends Alice a pizza containing a message to meet him. Jonas gets her to agree to a homing device in the pizza box and Jerry drives her with the box across the Queensboro bridge. He has made previous arrangements that enable him to ditch the agents following them, leaving the homing device behind. As he drives her to her father's private horse stables, Jerry tells her that he can almost remember what happened and is taking her to where "the music is playing." Alice turns on her mobile phone so they can still track her. At the stables Jerry remembers that he was sent to kill her father (a judge who was about to expose Jonas's operation) but found he couldn't kill him. Instead they became friends and Jerry promised to watch over Alice before the judge was killed by another assassin. She admits she switched the charts in the hospital. The CIA arrive and capture Jerry. Jonas gloats but Jerry says, "you've never seen her run." Alice outruns the men; a sniper misses her, killing the last guy chasing her, and she escapes.
Jonas tortures Jerry again. Meanwhile, Alice leads the FBI men (who are not actually FBI but from a "secret agency that watches the other agencies") to Jonas's office, but it has been entirely dismantled. Declining Lowry's help, Alice starts searching for Jerry. She realizes that a detail of Jerry's large mural is near a mental hospital and goes there. She bribes an attendant to show her an unused wing, breaks in through locked doors, and finds Jerry after hearing him singing through the ventilation ducts. As Jonas catches them, Lowry arrives with his men and attacks Jonas's men. Jerry attempts to drown Jonas but is shot once. In retaliation, Alice shoots Jonas dead. Alice tells Jerry she loves him as he is taken away in an ambulance.
Some time later, Alice visits Jerry's grave, leaving his union pin upon it, before returning to horse riding. As she rides away, Jerry, Lowry and Flip watching her. Jerry is not allowed to contact her until they are sure they have rounded up all of Jonas's other subjects. He secretly lets her know he is still alive by placing his union pin on her horse's saddle and the film ends.