In the 1980s, Professor Charles Xavier and Magneto visit a young Jean Grey (Famke Janssen) at her family home, hoping to persuade her to join their school, the X-Mansion. However, Jean's parents believe she is mentally ill and are all too willing to see her go. Unbeknownst to them, Jean possesses incredible abilities, which she demonstrates by levitating cars in the neighborhood with her mind—a clear indication of her powerful category 5 mutant potential.
Fast forward ten years, a troubled young Warren Worthington III (Ben Foster) is attempting to sever his wings, but his father, Warren Worthington II (Michael Murphy), is horrified upon discovering that his son is a mutant. The narrative shifts to the X-Men, who are engaged in a simulated battle against a colossal robot. Here, Kitty Pryde (Elliot Page), who can phase through matter, and Colossus (Daniel Cudmore), who can transform into organic steel, are part of the team. However, Cyclops (James Marsden) is missing from the lineup. In this high-stakes scenario, Storm (Halle Berry) emphasizes teamwork, yet Wolverine (Hugh Jackman) opts for a more reckless approach, relying on Colossus to launch him toward the robotic adversary, allowing him to sever the robot's head with his Adamantium claws. This action leads to tension between Storm and Logan.
Meanwhile, Beast (Kelsey Grammer) oversees the Department of Mutant Affairs, while Mystique (Rebecca Romijn) is imprisoned by the U.S. government after being caught stealing sensitive information regarding an experimental vaccine designed for mutants, which was developed from the DNA of Leech (Cameron Bright). Currently, the vaccine can only replicate the X-gene, not generate it.
Sometime later, Worthington Labs, under the leadership of Warren Worthington II, announces a new inoculation intended to suppress the X-gene. This controversial "cure" is offered to any mutant wishing to relinquish their powers, igniting a significant divide within the mutant community. As they announce the facility's location on Alcatraz Island, some mutants express interest in the cure, including Rogue (Anna Paquin), a young mutant who temporarily absorbs the abilities of anyone she touches. This creates tension when Iceman and Kitty's bond causes jealousy within Rogue, who longs for physical intimacy with Iceman but cannot due to her powers.
In retaliation to the vaccine's announcement, Magneto rallies an army, exclaiming that the "cure" is merely a guise for exterminating mutated beings. He reassembles his Brotherhood of Mutants, warning that the "cure" could be weaponized against their kind. With the support of Pyro, Callisto (a mutant endowed with superhuman senses), and several other mutants, Magneto launches an attack on the mobile prison, successfully liberating Mystique, Multiple Man (Eric Dane), and Juggernaut (Vinnie Jones). Tragically, during the rescue, Mystique is struck by a cure dart that eradicates her powers, leading to her abandonment by Magneto.
In a melancholic turn, Cyclops, still grieving the loss of Jean, returns to Alkali Lake, where he encounters her ghostly presence. Their moment of intimacy reveals Jean's darker side as she morphs into a fearsome figure. Recognizing peril, Professor X sends Wolverine and Storm to investigate. This leads them to a site marked by telekinetically moved objects, Cyclops's glasses, and an unconscious Jean. Professor X explains that Jean's previous sacrifice left her endowed with an alternate, sinister persona known as "Phoenix."
Xavier confesses to Wolverine that Jean's powerful abilities once required his telepathic restraint, resulting in Jean and Phoenix's split identities. Upon awakening, Jean begs Wolverine to end her life, but he refuses. As the Phoenix rises, she knocks Wolverine out before fleeing to her childhood home.
Meanwhile, Magneto and his cohorts scout Jean's location, surmising her immense potential. As he arrives at her home, Xavier leads his X-Men in pursuit. The two leaders clash over Jean's allegiance until Jean, as Phoenix, obliterates her family home, disintegrates Xavier, and departs with Magneto.
The X-Men realize Magneto plans to assault Alcatraz to eliminate Leech, the key to the "cure." They strategize to confront his forces, outnumbered yet determined. Magneto manipulates the Golden Gate Bridge to gain entry to Alcatraz, where Worthington Labs is situated. Armed military personnel meet this invasion with plastic "cure weapons" designed to neutralize mutants and counteract Magneto's magnetic prowess. Although the mutants suffer heavy losses initially, they soon gain the upper hand. The X-Men—Wolverine, Storm, Beast, Iceman, Colossus, and Shadowcat—engage Magneto and his forces in a fierce battle.
During the chaos, Beast administers the cure to Magneto, stripping him of his powers. Concurrently, Shadowcat infiltrates the facility to rescue Leech from the clutches of Juggernaut. As Phoenix rages, Wolverine, realizing his healing factor is his only advantage, steps up to confront her. Just as he reaches her, Jean temporarily regains control and implores Wolverine to save her, leading him to profess his love for her before he makes the heartbreaking decision to end her life.
In the aftermath of this tragic loss, the school continues under Storm's leadership, now the headmistress, with Wolverine taking on the role of teacher. The U.S. President appoints Beast as ambassador to the United Nations, and Rogue returns, revealing she has taken the cure, finally able to touch Iceman. In a reflective moment, Magneto, stripped of his abilities, sits quietly at a chessboard in a park, his fingers hovering over a chess piece that barely moves.
As an intriguing closing segment, a post-credits scene unfolds where Dr. Moira MacTaggert checks in on a comatose patient who eerily responds with Xavier’s voice, leaving her startled as she calls out, "Charles?"
