In an introduction three events are described (by an uncredited Ricky Jay) showing coincidences. The events, which are well-known urban legends in the universe of the film, are as follows:
Sir Edmund William Godfrey, a resident of Greenberry Hill, London, is murdered outside his pharmacy in an attempted robbery by three vagrants by the names Joseph Green, Stanley Berry, and Daniel Hill. This was based on the murder of Edmund Berry Godfrey.
A blackjack dealer, Delmer Darion, while scuba diving in a lake, is accidentally scooped up by a fire fighting airplane as it fills its tank with water to drop on a forest fire, and he dies of a heart attack as a result of his plight. The pilot of the water-dropping plane, Craig Hansen, had encountered Darion a few days prior, at the latter's casino, and started a fight with him after losing a hand of blackjack. The guilt and the measure of coincidence provokes the pilot, Hansen, to commit suicide.
A 17-year-old boy, Sydney Barringer, attempts suicide by jumping off the roof of his apartment building; this attempt became a "successful homicide" when he was accidentally shot by his mother (Miriam Margolyes) as he fell past his own apartment window. His parents regularly argued and threatened each other with a shotgun that was normally kept unloaded. Unbeknownst to them, Sydney had loaded the gun a few days earlier hoping they would make good on their threats to kill one another. As a result, he unwittingly became an accomplice in his own murder. The irony is that a newly installed protective netting for window washers on the building's exterior below their apartment would have saved his life if he had not been hit by the shotgun blast that he himself had loaded.
Forthright police officer Jim Kurring (John C. Reilly) is called to investigate a disturbance at the home of a woman named Marcie (Cleo King). He finds a body in her closet, but when the other police officers arrive they pay little attention to his report on the situation. A young boy, Dixon (Emmanuel Johnson) offers to help Jim with the case by performing a self-penned rap. Dixon claims that in the words of the rap he told Jim who committed the murder, but, thinking the boy is just joking, Jim ignores him.
Former TV producer Earl Partridge (Jason Robards) is in the final stages of cancer, and is being cared for by a nurse, Phil Parma (Philip Seymour Hoffman), while his young trophy wife Linda (Julianne Moore) is out collecting prescriptions for a strong dose of liquid morphine that will end his pain. Earl mentions to Phil that he has an estranged son and asks him to find him, saying his name is Frank Mackey. Phil, aware that Mackey is the author of the "Seduce And Destroy" self-help system for men, orders in some pornographic magazines, hoping to find a phone number for his self-help system in there. Frank Mackey (Tom Cruise) is giving a seminar to an audience of men, instructing them how they can manipulate women into "sleeping" with them. As his seminar breaks for lunch, a reporter named Gwenovier (April Grace) takes him aside to interview him. He is initially very confident in his interview, but tells Gwenovier that his father is dead.
Claudia Wilson (Melora Walters) is visited by her father, gameshow host Jimmy Gator (Philip Baker Hall), who tries to inform her that he is dying of cancer. However, Claudia is enraged at the sight of him and orders him to leave her apartment. Back at the TV studio, Jimmy informs his wife Rose (Melinda Dillon) by phone of how Claudia "went crazy." One of the young contestants of Jimmy's gameshow, "What Do Kids Know?", Stanley Spector (Jeremy Blackman) arrives at the studio with his neglectful father Rick (Michael Bowen). Whereas the other child contestants are only interested in the fame that comes with being on TV, Stanley is genuinely erudite, but his father encourages him only because he wants the prize money. A former champion of the show in the 1960s, Donnie Smith (William H. Macy) is now working in a department store and is fired by his boss, Solomon Solomon (Alfred Molina) for not making enough sales. Donnie protests, saying he needs money for his "corrective oral surgery," though Solomon tells him he has no need for braces.
Jim (the police officer) is now called to the home of Claudia, after her row with Jimmy earlier has been reported as a disturbance. Jim is immediately attracted to her, and tries to prolong the visit, though he is somewhat awkward at making any advances, and she too is awkward, partly as she is trying to hide any evidence of her drug habit from him, and partly because she is so unused to anyone being so kind to her. Eventually, Jim is called away on another task but before he goes he asks Claudia if she will go on a date with him and she agrees. Meanwhile, Linda collects the various drugs at a pharmacy, but the clerk makes joking remarks insinuating they are for recreational use. Infuriated, Linda chastises him for making judgments on her life when he doesn't know her. She then goes to see Earl's lawyer, Alan Kligman (Michael Murphy), begging him to change Earl's will. She states that she originally married Earl for his money, but has grown to love him, and wants none of his money to avoid the guilt of what she's done. Alan says there's nothing he can do.
The game show finally gets underway, and Stanley's keen intelligence provides the kids with a good start on the adults. However, in a commercial break the producers refuse to let Stanley go to the bathroom. When the game continues he wets himself and stops answering questions out of embarrassment, causing the adults to begin to win. Jimmy feels progressively more ill as the show continues, until he collapses on stage. He orders his friend Burt Ramsey (Ricky Jay) to go on with the show, and in the break, Rick is furious with Stanley for not answering the questions. As the game goes on, Jimmy asks Stanley to come out for the final round, but Stanley refuses, and now asks Jimmy why he should be made to feel like a "doll" just because he is intelligent. Jimmy replies that he doesn't know and the show goes to the credits.
Meanwhile, Gwenovier becomes more curious about Frank's past. Her information shows that Frank's mother died in 1980 and that he had to care for her as she became ill because his father, Earl, wasn't around. Frank becomes deeply insulted at her attempts to probe into his past and refuses to talk for the remainder of the interview. Phil, having called the help-line for Seduce and Destroy, has finally gotten through to Frank's personal assistant. She gives the message to Frank, who, after the interview, is very unhinged. However, Linda gets back and hangs up Phil's phone call, telling him not to get involved in family business, for which Phil apologizes. Meanwhile Donnie heads to a bar that he frequents, mainly so he can watch Brad the bartender (Craig Kvinsland), with whom he is infatuated. Brad has braces, and it is because of this that Donnie is trying to get some himself in hopes that it will somehow make Brad love him. Seeing Brad talking to a barfly, Thurston Howell (Henry Gibson), Donnie talks to Howell and asks him if he has love in his heart. Howell is unsympathetic to Donnie, mocking his stupidity, and Donnie becomes morose remembering how his parents took the money he won on the game show. Driven to desperation, Donnie confesses his love for Brad and storms out.
Jim, driving away from Claudia's, is excited about the date he has arranged. He investigates a jaywalker who seems suspicious. However, as he investigates, a mysterious assailant fires a gun at him, causing him to drop his. The gun is stolen by Dixon, leaving Jim feeling stupid at having lost his gun and terrified of being the laughingstock of his colleagues. Meanwhile, Linda apologizes to Phil for shouting at him and tells him to apologize to Earl for her, then goes out to the car and takes all of the medication she got for Earl, attempting suicide. Lapsing back into consciousness, Earl tells Phil the story of his first love, Lily, whom he loved but cheated on. He tells him of his regret for all the stupid things he did in his life.
Jim and Claudia go on their date, and early on they promise not to lie to each other, to be frank and honest so they can get through the troubles that harm other relationships. Jim confesses to having lost his gun and that he hasn't been on a date since he was married. Claudia seems terrified of committing to conversation with him, claiming that he will hate her when he finds out more about her. She claims she has problems, but Jim assures her that he doesn't care. He kisses her, but she runs off, leaving Jim bewildered.
Jimmy is taken home to Rose, who looks after him, but he then tries to talk to her seriously, saying he has cheated on her and he wanted to be honest. Rose asks him why Claudia doesn't talk to him, and Jimmy replies that she thinks he molested her, but he can't remember if he did or not. Appalled, Rose leaves the house and Jimmy decides to kill himself, taking a gun from the kitchen.
Donnie decides to get revenge on Solomon by using copies of his keys to break in and steal money from the safe. He is successful in this, but breaks his key in the lock as he heads back to the car. After driving away, he suddenly realizes the foolishness of what he is doing, he goes back to replace the money but finds he cannot get back in having broken the key. Instead, he begins to climb a utility pole to try to get in through the roof. Dixon, meanwhile, finds Linda near death in her car. After taking some money from her purse he calls an ambulance and again recites his rap as the paramedics take her away. Having thought over the phone call earlier, Frank arrives at Earl's house and is shown through to Earl by Phil. Watching Earl die, Frank is consumed by sadness and hatred, not knowing what to say to the man who ruined his life. Jim drives morosely back home after his failed date and sees Donnie climbing the utility pole and goes to stop him.
Just then, frogs suddenly start to rain from the sky. As Rose drives through the rain of frogs, she crashes her car outside Claudia's apartment and runs in fear to a reconciliation with her daughter. As Jimmy is about to kill himself, the frogs fall through his skylight and cause him instead to shoot the TV, meaning his house begins to catch fire - whether he survives is never made clear. The frogs cause Donnie to fall from the pole, smashing his teeth, eliminating his need for braces. The rain of frogs abruptly ceases with a final incongruous object - Jim's gun falls from the sky and lands right in front of him. Jim helps Donnie replace the money and to forgive himself - Jim chooses to act in forgiveness, rather than in duty, which would have compelled him to arrest Donnie. Having been given the liquid morphine by Phil, Earl dies as Frank watches (the two of them perhaps finally reconciled). Frank then goes to the hospital to see Linda, who is making a gradual recovery. Stanley goes to his father and tells him that he needs to be nicer to him. Rick curtly responds by telling Stanley to go to bed. The film ends as, the next morning, Jim goes to visit Claudia. He talks to her, telling her that he wants to be honest with her as she told him to, and he wants to make things work out between them. She breaks the fourth wall and smiles at the camera.
