I see angels, Mickey. They're comin' down for us from heaven. And I see you  

          ridin' a big red horse, and you're driving them horses, whippin' 'em, and the're

         spitting and frothing all 'long the mouth, and the're coming right at us. And I

                see the future, and there's no death, 'cause you and I, we're angels...

The film opens with Mickey Knox (Harrelson) and his girlfriend Mallory (Lewis) in a roadside cafe. Mallory is offended when a local tries to hit on her. He asks her to dance, she dances for a short while. Mallory then punches him in the face and kicks him several times, embarrassing him. He tries to fight back, but is easily put down by Mallory. She jumps on him and stamps on his face to kill him. Mickey, meanwhile, stabs two other customers and shoots the chef and the waitress (with a drawn-out bulletime sequence). They leave one witness alive, as is their custom, to "tell the tale....."

After the titles, there is a flashback sequence as to how the murderous pair met up: Mickey was a delivery man who turned up at the house where Mallory lived with her physically and sexually abusive father, her mother, and Kevin, her younger brother. The scene is portrayed as a sitcom, the "audience" laughing hardest when Mallory is subjected to lewd comments and molestation by her repulsive father. When Mickey arrives with a delivery of beef, he falls in love with Mallory and whisks her away on a date, stealing her father's car in the process. Mickey is arrested and imprisoned for car-theft, but escapes and returns to Mallory's house. The two kill her father by drowning him in the fishtank, and burn her mother alive in her bed. They spare her ten-year-old brother. Mickey then takes Mallory away with him.....

Back in the present the pair continue their crime-spree, slaughtering their way across the southwest United States and ultimately claiming fifty-two victims. Following them are two characters who have an obsessive interest in Mickey and Mallory for the purposes of acquiring fame and glory, as well as furthering their own careers. The first is a policeman, Detective Jack Scagnetti (Sizemore), who is seemingly in love with Mallory. Scagnetti wants to achieve hero status by capturing the pair, though it is plainly revealed that Scagnetti has a lifelong obsession with serial killers after seeing his mother shot and killed by Charles Whitman when he was five. The second is journalist Wayne Gale (Downey), who hosts a show called 'American Maniacs', profiling serial killers in a blatantly sensationalist way. Various clips of his program on Mickey and Mallory are shown, with Gale sounding outraged as he details the pair's crimes, although off-air he clearly regards their crimes as a fantastic way of boosting his show's ratings. It is Gale who is mostly responsible for elevating Mickey and Mallory into heroes.

While lost in the desert, Mickey and Mallory are taken in by a Navajo man (known as "Old Indian") and his grandson. After the duo fall asleep, the Old Indian begins chanting beside the fire, invoking nightmares in Mickey about his abusive father and mother. Mickey wakes up in a rage and shoots Old Indian before he realizes what he is doing. Mallory and Mickey are both traumatized, marking the first time the couple feel guilty for a murder. Mallory exclaims, "You killed life!" implying Old Indian was more worthy of living than their previous victims. While running from the scene through the desert, the two are bitten repeatedly by rattlesnakes.

They go to a drugstore to find snakebite antidote, but the police interfere and a gunfight ensues, ending when Scagnetti captures them at gunpoint. The film then jumps ahead one year. After a surreal trial that is shown in a flashback in clips from 'American Maniacs', the homicidal couple have been imprisoned but are shortly due to be shipped to a mental hospital after being declared insane.

Scagnetti arrives at the prison and meets up with Warden McClusky and the two devise a plan to get rid of Mickey and Mallory: McClusky will arrange for Scagnetti to transport the Knoxs to the mental hospital. Alone with the pair during transport, Scagnetti will shoot and kill them claiming that they were trying to escape. Gale is also at the prison and persuades Mickey to agree to a live interview to air immediately after the Super Bowl. At the time, Mallory is held in solitary confinement elsewhere in the prison, awaiting her transport to the mental hospital. As planned, Mickey is interviewed by Gale. He gives a speech about how crime is a normal part of humanity, describes enlightenment through murder and declares himself a "natural born killer." His words inspire the other inmates (who are watching the interview on TV in the recreation room) and incite them to riot. During the riot, the inmates subdue, torture, and murder nearly all of the prison guards and their inmate informants.

Warden McClusky heads down to the control room, leaving Mickey alone with Gale, the film crew and several guards. Using a lengthy joke complete with hand gestures as a diversion, Mickey elbow-smashes a guard in the face and steals his shotgun. Mickey kills most of the guards and takes the survivors and film crew hostage. He leads them through the prison riot to find Mallory. Gale follows, giving a live television interview as people are slaughtered all around him. Meanwhile, Mallory is being savagely beaten in her cell by Scagnetti for refusing to submit to his attempts at seduction (for which she attacked him). Still live on national television, Mickey engages in a short stand off with Scagnetti, eventually feigning concession to lower Scagnetti's guard. Scagnetti is then brutally killed by Mallory.

After being rescued by a mysterious prisoner named Owen, Mickey and Mallory take cover in a blood-splattered shower-room. By this time Gale has snapped and has shot a number of prison guards himself, finding the killing a thrill. Warden McClusky is outside the shower room with dozens of guards. Obsessed with killing Mickey and Mallory, McClusky threatens to storm the shower room, despite the protests of his guards who insist that there are more pressing problems, namely the hundreds of other rioting inmates heading their way.

Mickey and Mallory, together with their savior, Owen, eventually manage to escape, holding guns to the heads of Wayne Gale and a prison-guard hostage, Gale's camera still capturing everything. After Mickey and Mallory flee, McClusky and his guards are massacred by hordes of inmates who eventually burst through into the area. In the director's cut of the film, there is a shot of McClusky's head on a pike.

In a rural location Mickey and Mallory give a final interview to Wayne Gale before - much to his surprise and horror - they execute him, capturing it on the camera (their one survivor). The couple are then shown in an RV together, with Mickey driving and Mallory watching their two children play.

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