In Sydney, bio-genetics scientist Dr. Vladimir Nekhorvich sends a message to the IMF for Dimitri (Ethan Hunt's cover name), his old friend, warning that his employer, Biocyte Pharmaceuticals, forced him to develop a biological weapon, the Chimera virus, to profit from the cure, Bellerophon. He injects himself with the virus, carrying Bellerophon in a bag. However, en route to Atlanta, IMF agent Sean Ambrose, who was disguised as Dimitri, goes rogue, betrays Nekhorvich, steals Bellerophon, and crashes the plane in the Rockies.

In Seville, IMF director Swanbeck informs Ethan about Ambrose's actions, tasks him with recovering Chimera and Bellerophon, and has him recruit Nyah Nordoff-Hall, a professional thief and Ambrose's ex-girlfriend. Despite her initial reluctance, Ethan gets her to trace Ambrose to Sydney using an injectable tracking device. Ethan assembles his team, old friend and computer hacker Luther Stickell and helicopter pilot Billy Baird, in Sydney while Nyah pretends to rekindle her relationship with Ambrose.

After Ambrose uses a video of Chimera infecting one of Nekhorvich's colleagues to blackmail Biocyte's CEO, John McCloy, into cooperation, Nyah gives Ethan the memory card containing the video, revealing that Chimera has a 20-hour dormant period; Bellerophon is only effective if used within that window. Ethan's team kidnaps McCloy and learns that the only Bellerophon samples, taken by Nekhorvich, are now in Ambrose's hands, but he doesn't have the virus, since Nekhorvich injected himself with it. Ethan breaks into Biocyte headquarters and destroys two samples of Chimera, but Ambrose's team ambushes him, having discovered Nyah's deception. At a stalemate, Ambrose orders Nyah to retrieve the virus' last sample, but she injects herself with it instead and begs Ethan to kill her to destroy the virus. Ethan refuses and flees the facility, promising to get her the cure.

Ambrose releases Nyah to wander the streets of Sydney, intending to start a pandemic. He offers to sell Bellerophon to McCloy in exchange for enough stock options to make him Biocyte's majority shareholder, enabling both him and McCloy to make billions. Ethan infiltrates Ambrose's base and fights Ambrose's right-hand man Hugh Stamp; Stamp seemingly brings a subdued Ethan to Ambrose, who executes him. However, Ambrose discovers that the dead "Ethan" is actually Stamp, masked and gagged, while the real Ethan has stolen the Bellerophon samples. Enraged, Ambrose and his men chase after Ethan, who kills them, while Luther and Billy locate Nyah, who has wandered to a cliffside to kill herself and prevent the outbreak.

Ethan kills Ambrose in a fistfight on the beach and gives Bellerophon to the arriving Luther, who injects Nyah with it. The IMF clears Nyah's criminal record and Ethan starts a vacation with her in Sydney.

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