Dr. Vladimir Nekhorvich, a bio-genetics scientist, sends a message to the IMF for Dimitri (Ethan Hunt's cover name), his old friend. He warns that his employer, Biocyte Pharmaceuticals, forced him to develop a biological weapon to profit from the cure. He injects himself with the Chimera virus and carries its remedy Bellerophon in a bag. However, IMF agent Sean Ambrose, who was disguised as Dimitri, goes rogue, betrays Nekhorvich, and steals Bellerophon.
IMF director Swanbeck informs Ethan about Ambrose's actions and tasks him with recovering the virus and its cure. He 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, where Biocyte laboratories are located; this is achieved by her wearing an injectable tracking device. Ethan assembles his team, old friend and computer hacker Luther Stickell and helicopter pilot Billy Baird, and heads to Sydney while Nyah pretends to rekindle her relationship with Ambrose. Ambrose meets with Biocyte's CEO, John McCloy, and shows him a video of Chimera infecting one of Nekhorvich's colleagues before blackmailing McCloy into cooperating with him.
Nyah steals the memory card containing the video and delivers it to Ethan. They learn that Chimera has a 20-hour dormant period, and Bellerophon is only effective if used within that window. When Nyah returns the memory card to Ambrose, she places it in the wrong pocket of his jacket. Ethan's team kidnaps McCloy and learns that the only Bellerophon samples were taken by Nekhorvich and are in Ambrose's hands. However, Ambrose does not have the virus, which Nekhorvich injected himself with. Ethan prepares to break into Biocyte headquarters to destroy the virus samples, but Ambrose, posing as Ethan via disguise, tricks Nyah into revealing their plan.
Ethan destroys all but one sample of Chimera before Ambrose's team engages him in a firefight. At a stalemate, Ambrose orders Nyah to retrieve the virus, 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 stock options to make him billions as Biocyte's majority shareholder. Ethan infiltrates Ambrose's base and engages in a fight with Ambrose's right-hand man Hugh Stamp, with the latter seemingly winning. Hugh brings a subdued Ethan to Ambrose, who executes him. However, Ambrose discovers that the dead "Ethan" is actually Stamp, while the real Ethan had stolen the remaining Bellerophon samples. Enraged, Ambrose and his men chase after Ethan. Meanwhile, Luther and Billy locate Nyah, who has wandered to a cliffside to kill herself and prevent an outbreak.
After a long chase, Ethan kills most of Ambrose's men. He subdues Ambrose in a fistfight on the beach and later shoots him in self-defense. Luther arrives at the beach, acquires Bellerophon from Ethan, and injects Nyah with it. The IMF clears Nyah's criminal record and Ethan starts a vacation with her in Sydney.
