In 1976 television presenter Tony Wilson sees the Sex Pistols perform at the Manchester Lesser Free Trade Hall for the first time. Inspired, Wilson starts a weekly series of punk rock shows at a Manchester club, where the newly formed Joy Division perform, led by the erratic, brooding Ian Curtis. Wilson founds a record label, Factory Records, and signs Joy Division as the first band; the contract is written in Wilson's blood and gives the Factory artists full control over their music. He hires irascible producer Martin Hannett to record Joy Division, and soon the band and label have a hit record. In 1980, just before Joy Division is to tour the United States, Curtis hangs himself. Joy Division rename themselves New Order and record a hit single, " Blue Monday ". Wilson opens a nightclub, the Haçienda; business is slow at first, but eventually the club is packed each night. Wilson signs another hit band, Happy Mondays, led by Shaun Ryder, and the ecstasy -fuelled rave culture is born. Despite the apparent success, Factory Records is losing money. Every copy of "Blue Monday" sold loses five pence, as the intricate packaging by Peter Saville costs more than the single's sale price. Wilson pays for New Order to record a new album in Ibiza, but after two years, they still have not delivered a record. He pays for the Happy Mondays to record their fourth studio album in Barbados, but Ryder spends all the money on drugs. When Wilson finally receives the album, he finds that Ryder has refused to record vocals, and all the tracks are instrumentals. At the Haçienda, ecstasy use is curbing alcohol sales and attracting gang violence. The Factory partners try to save the business by selling the label to London Records. However, Wilson reveals that the Factory does not hold contracts with any of its artists and, therefore, does not own a catalogue of recordings. This renders the company ultimately worthless and the deal falls through. While smoking marijuana on the roof of Haçienda after its closing night, Wilson has a vision of God, who assures Wilson he has earned a place in history.

In 1967, Edward Jessup is a Columbia University psychopathologist studying schizophrenia. He thinks that "our other states of consciousness are as real as our waking states." He begins experimenting with sensory deprivation using a flotation tank, aided by like-minded researchers, Arthur Rosenberg and Mason Parrish. At a faculty party, he meets fellow "whiz kid" and his future wife, Emily. Over a decade later, Edward is a tenured professor at Harvard Medical School. He and Emily have two daughters and are on the brink of divorce when they reunite – for the first time in seven years – with the couple who had first introduced them. When Edward hears about the Hinchi tribe, whose members experience shared hallucinatory states, he decides to travel to Mexico in order to participate in their ceremony. During the climb up into the Hinchi hill country (a plateau covered in spectacular mushroom-shaped ventifacts), Edward is told by his guide, Eduardo Echeverria, that the Hinchi use in their ceremonies a potion containing the sacred mushroom Amanita muscaria and the shrub sinicuiche, which they are collecting for next year's ceremonies. The tribe calls sinicuiche by a Hinchi name meaning "first/primordial flower" in recognition of the deep memory states which it can evoke. An indigenous elder ("the brujo ") is seen with a root in his hand, which he asks Edward to hold, before cutting Edward's hand in order to add drops of blood to the mixture he is preparing. Immediately after consuming the mixture, Edward experiences bizarre, intense hallucinations, including one of the petrifaction and subsequent erosion by blown sand of Emily and himself. The following morning, Edward leaves the Hinchi plateau under a cloud, having killed, while in his intoxicated state, a large specimen of the Hinchi's sacred monitor lizard. He returns to the U.S. with a sample of the Hinchi potion for analysis by his colleagues and further self-experimentation and continues taking it in order to take his exploration of altered states of consciousness to a higher level. When toxic concentrations of the substance make increased dosage dangerous, Edward returns to sensory deprivation, believing it will enhance the effects of the substance at his current dose. Repairing a disused tank, he uses it to experience a series of increasingly drastic visions, including one of early Hominidae. Monitored by his colleagues, Edward insists that his visions have "externalized". Emerging from the tank, his mouth bloody, frantically writing notes because he is unable to speak, he insists on being X-rayed before he "reconstitutes." A radiologist inspecting the X-rays says they belong to a gorilla. In later experiments, Edward experiences actual, physical biological devolution. At one stage, he emerges from the isolation tank as a feral and curiously small-statured, light-skinned caveman, going on a rampage in town and breaking into a zoo before returning to his natural form. In the final experiment, he experiences a more profound regression, transforming into an amorphous mass of conscious, primordial matter. An energy wave released from the experiment stuns Edward's colleagues and destroys his tank. Emily recovers and finds a swirling maelstrom where the tank had been. She searches in the vortex for Edward, finding him as he is on the brink of becoming a non-corporeal energy being that will vanish from reality if this transformation reaches its conclusion. His friends bring Edward home, hoping that the transformations will end. Watched over by Emily, Edward begins to regress uncontrollably, the transformations no longer requiring the intake of "first flower" or sensory deprivation. Urging Edward to fight the change, Emily grabs his hand, being enveloped by the primordial energy emanating from him. The sight of Emily apparently being consumed by the energy stirs the human consciousness in Edward's devolving form. He fights the transformation off by banging repeatedly into the hallway wall and returns to his human form. Edward then grabs Emily's form, and she returns to normal. The movie ends with the two on the floor in a nude embrace as Edward tells Emily that he loves her, which she had longed to hear him say.

Nine years have passed since the failure of the Discovery mission to Jupiter in 2001, in which commander David Bowman and his crew were lost. Amid international tensions, the United States and Soviet Union each prepare separate missions to Jupiter. The Soviet spacecraft Leonov will be ready a year before the American Discovery Two, but only the Americans can reactivate the ship's sentient computer, HAL 9000, thought to be responsible for the disaster. Because Discovery will crash into Jupiter's moon Io before the Americans can reach it, the Soviets agree to bring along former NCA Director Heywood Floyd, Discovery engineer Walter Curnow, and HAL 9000 creator Dr. Chandra. Arriving at Jupiter, Leonov detects chlorophyll on Jupiter's icy moon Europa. A probe sent to investigate is destroyed by an energy burst upon reaching the source of the chlorophyll. Floyd suggests that this is a warning to stay away from Europa. After aerobraking in Jupiter's atmosphere, Leonov enters orbit around Io and encounters Discovery. Curnow and Cosmonaut Max Brailovsky spacewalk to and enter the derelict vessel. Both men suffer panic attacks for different reasons, bonding over the shared experience and becoming friends. Curnow restores Discovery ' s power and propulsion, and Chandra reactivates HAL. The ships move to investigate the giant monolith located at the Lagrange point between Jupiter and Io. Brailovsky approaches it in an EVA pod, but is killed when the pod is destroyed by an energy burst. On Earth, Bowman, now a noncorporeal being, appears through his former wife's television to say goodbye, telling her that "something wonderful" is going to happen. He then visits his comatose mother in a hospital, and she awakens, seemingly aware of her son's presence. The unseen Bowman brushes her hair, and after he departs, she dies peacefully. Chandra discovers the reasons for HAL's malfunction: the National Security Council ordered HAL to conceal information about the monolith from Discovery ' s crew. This conflicted with HAL's basic programming, causing the computer equivalent of a paranoid breakdown. When Bowman and co-pilot Frank Poole discussed deactivating the malfunctioning computer, HAL concluded that the human crew was endangering the mission, and terminated them. Chandra blames Floyd, who denies any knowledge of the order, although it bears his signature. A political crisis on Earth brings the United States and the Soviet Union to the brink of war. The Americans are thus ordered to leave Leonov for Discovery. Both ships plan to leave Jupiter in the coming weeks, but Bowman appears to Floyd to warn him that everyone must leave within two days. Floyd returns to Leonov to convince Soviet captain Tanya Kirbuk to leave early. Neither ship has the fuel to reach Earth if they leave ahead of schedule, but Floyd proposes using Discovery as a booster rocket, then leaving it behind while both crews escape on Leonov. As they argue, the monolith suddenly disappears. Alarmed, Kirbuk agrees to Floyd's plan. An ominous black spot appears in Jupiter's atmosphere. HAL determines that the spot is a vast group of monoliths, multiplying exponentially and altering Jupiter's mass and chemical composition. He recommends halting the countdown to study the phenomenon. Floyd worries that HAL will prioritize his mission over the safety of the human crews, but Chandra reveals to HAL that the crew is in danger and that both ships could be destroyed. HAL thanks Chandra for telling him the truth, and proceeds with the escape plan. Once Discovery ' s fuel is exhausted, Leonov separates and fires its own engines. Bowman asks HAL to transmit a message to Earth. The monoliths engulf Jupiter, causing it to undergo nuclear fusion, and become a star. Before Discovery is destroyed, HAL sends this message: ALL THESE WORLDS ARE YOURS EXCEPT EUROPA ATTEMPT NO LANDING THERE USE THEM TOGETHER USE THEM IN PEACE Leonov survives the shockwave from Jupiter's ignition, and returns home. Floyd narrates how the new star's miraculous appearance, and the message from a mysterious alien power, inspire the American and Soviet leaders to seek peace. Under its infant sun, icy Europa transforms into a humid jungle, covered with life, and watched over by a monolith.

Rhoda Williams, a brilliant 17-year-old girl who has spent her young life fascinated by astronomy, is delighted to learn that she has been accepted into MIT. She celebrates, drinking with friends, and in a reckless moment, drives home intoxicated. Listening to a story on the radio about a recently discovered Earth -like planet, she gazes out her car window at the stars and inadvertently hits a stopped car at an intersection, putting John Burroughs in a coma and killing his pregnant wife and young son. After serving her four-year prison sentence, Rhoda becomes a janitor at her former high school and struggles with guilt and regret. Hearing more news stories about Earth 2, Rhoda enters an essay contest sponsored by a millionaire entrepreneur who is offering a civilian space flight to Earth 2. One day Rhoda sees John laying a toy at the accident site. She visits his house, intending to apologize. He answers the door and she loses her nerve. Instead, she pretends to be a maid offering a free day of cleaning as a marketing tool for a cleaning service. John, who has dropped out of his Yale music faculty position, has been letting his home and himself go, and accepts Rhoda's offer. He has no idea who she is, and when she finishes asks her to come back the next week. In time, a caring relationship develops and they have sex. Rhoda wins the essay contest and is chosen to be one of the first to travel to Earth 2. John asks her not to go, believing they might have a future together. She finally decides to tell him the truth about who she is. He is upset and throws her out of the house. Rhoda hears an astrophysicist talking on television, describing a "broken mirror" hypothesis which states that upon the sighting of Earth 2 the synchronicity of events happening in both the Earths was broken. Rhoda rushes back to John's house, but he refuses to let her in. She breaks into his house, and he begins to strangle her. He stops, and when she recovers she tells him about the theory and that there might be a possibility for his family to still be alive on Earth 2 and leaves him the ticket. In time, she learns that John accepted the gift and becomes one of the first civilian space travelers to Earth 2. Four months later, on a foggy day, Rhoda approaches her house, discovering her other self from Earth 2 standing in front of her.