Craig Schwartz, portrayed by John Cusack, is a down-on-his-luck puppeteer navigating the struggles of an unfulfilling marriage with his pet-obsessed wife, Lotte, played by Cameron Diaz. When he manages to secure a job as a file clerk at LesterCorp, thanks to Dr. Lester, he finds himself in the peculiar low-ceilinged second floor offices of the Mertin Flemmer Building in New York City. There, he becomes infatuated with his colleague, Maxine, brought to life through the talents of Catherine Keener, but unfortunately, his feelings are not reciprocated.
In a bizarre twist of fate, Schwartz discovers a mysterious small door hidden behind a filing cabinet, which transports him into the mind of actor John Malkovich. For a brief fifteen minutes, he can experience the world through Malkovich's perspective, only to be unceremoniously ejected and discarded into a ditch alongside the New Jersey Turnpike. Intrigued, he reveals the doorway to Maxine, and together, they hatch a scheme to monetize the experience, charging users $200 each.
Lotte soon learns about the portal and becomes infatuated with the feeling of living vicariously through Malkovich, which allows her to explore her transgender aspirations. This twisted love triangle escalates as Lotte develops feelings for Maxine, resulting in a sexual relationship involving Malkovich. Feeling abandoned and betrayed by both women, Schwartz resorts to locking Lotte in a cage. Meanwhile, unbeknownst to Maxine, Schwartz manipulates Malkovich’s body to engage with her, causing the actor to spiral into paranoia as he grapples with losing control over his own identity.
The narrative thickens as Malkovich seeks the truth, following Maxine back to the Mertin Flemmer building. He unwittingly tries the portal, finding himself trapped in a surreal realm where everyone appears as him, repeating “Malkovich” ad infinitum. After a chaotic encounter, he meets Schwartz again on the turnpike, demanding the closure of the portal, only to find him unwilling to comply.
As the plot races forward, Lotte manages a daring escape to alert Maxine about Schwartz’s actions. Initially annoyed, Maxine accepts the arrangement as she had secretly relished the experience. In her quest for answers, Lotte seeks the guidance of Dr. Lester, who is privy to the portal's secrets and has a dedicated room full of Malkovich memorabilia. He explains the precarious nature of ownership over the portal, revealing that on the eve of turning 44, the connection becomes available for inhabitation by another, and thereafter transfers to an unborn entity.
In the meantime, Schwartz capitalizes on his newfound control, living inside Malkovich's body for eight months, transforming him into a celebrated puppeteer and even marrying Maxine. However, their relationship begins to fray as Malkovich's 44th birthday looms, prompting Dr. Lester to formulate a plan involving blackmail against Maxine to manipulate Schwartz into relinquishing control.
In a desperate twist of fate, Lotte, consumed by hopelessness, plots to end Maxine's life. The chaos leads to a confrontation at the turnpike, diving into Malkovich's subconscious. Maxine reveals a shocking truth about her pregnancy, stemming from her time spent with Lotte within Malkovich, solidifying their bond amid the upheaval.
Ultimately, Schwartz makes the agonizing choice to exit Malkovich's persona, yearning to win back Maxine. But just as Malkovich regains control, Lester and his associates ensnare him again, leading Schwartz to find himself spun into a new and unintended reality—now inhabiting the body of Maxine's and Lotte's child, Emily. In this new existence, Schwartz is condemned to spend 40 years as a mere spectator in the lives of Lotte and Maxine, unwittingly observing their happiness from behind Emily's eyes. Meanwhile, an elder Malkovich, now subjugated by Dr. Lester's group, envisions a future anchored in exploiting Emily for the sake of eternal life.
