Bio-chemical expert Dr. Vladimir Nekhorvich sends a message to the IMF for Ethan Hunt, an old friend of his, warning that his employer, Biocyte Pharmaceuticals, forced him to develop a biological epidemic to profit from its remedy. He arranges to meet with Ethan to deliver the Chimera virus, and its cure, Bellerophon. With Ethan on vacation and incommunicado, the IMF sends agent Sean Ambrose disguised as Ethan to meet Nekhorvich on a passenger plane. Ambrose goes rogue, killing Nekhorvich and stealing Bellerophon before his men destroy the plane.
IMF Commander Swanbeck informs Ethan of the circumstances of Nekhorvich’s death and they determine Ambrose is responsible. Swanbeck tasks Ethan with recovering the virus and its cure, and has him recruit Nyah Nordoff-Hall, a professional thief presently operating in Seville, Spain. Nyah was recruited as a part of the team to trace Ambrose and his team and kill them since she is Ambrose’s ex-girlfriend. Ethan reluctantly convinces her to spy on Ambrose.
Ethan assembles his team, computer expert Luther Stickell and pilot Billy Baird, in Sydney, Australia, where Biocyte laboratories are located and Ambrose is staying. As Ethan stakes out Biocyte, Nyah rekindles her former relationship with Ambrose and relays information to Ethan’s team. At a horse racing event, Ambrose meets with Biocyte’s CEO, John C. McCloy. He shows McCloy a memory card video of Chimera affecting one of Nekhorvich’s colleagues before blackmailing McCloy into cooperating with him. Nyah steals the camera’s memory card and delivers it to Ethan. They learn that Chimera has a 20-hour dormant period before it causes death by mass destruction of the victim’s red blood cells. Bellerophon can only save the victim if used within that 20-hour window. When Nyah discreetly returns the memory card to Ambrose, he notices it is in the wrong pocket of his jacket.
Ethan’s team kidnaps McCloy to force him to give up Bellerophon. However, the only Bellerophon samples were taken by Nekhorvich, and are now in Ambrose’s hands. Ambrose has the cure, but does not have the virus; unbeknownst to him at the time, Nekhorvich injected himself with Chimera to smuggle it out of Biocyte. Ambrose plans to exchange a sample of Bellerophon to McCloy for a sample of Chimera. Ethan’s team breaks into Biocyte to destroy the virus before the exchange can take place. Ambrose, posing as Ethan, tricks Nyah into revealing the plan, then captures Nyah and raids Biocyte to secure the virus. Ethan is able to destroy all but one sample of Chimera before Ambrose intervenes, and a firefight ensues, culminating in the sample being dropped on the floor between Ambrose and Ethan. Ambrose orders Nyah to retrieve the sample; she instead injects herself with it, preventing Ambrose from simply killing her after she retrieved it for him. Nyah insists that Ethan kill her to destroy the virus but Ethan is unwilling to do so. Ambrose takes Nyah away as Ethan escapes from the laboratory.
Ambrose releases Nyah to wander the streets of Sydney in a daze, intending to start a pandemic. He offers to sell Bellerophon to McCloy in exchange for stock options, to make him Biocyte’s majority shareholder. He predicts that the price of Biocyte’s stock will skyrocket due to demand for Bellerophon after the Chimera outbreak. Ethan infiltrates the meeting and steals the remaining samples of Bellerophon. While Ethan is pursued by Ambrose’s men, Luther and Billy locate Nyah, who has wandered to a cliff side, intent on killing herself to prevent the eventual outbreak. Ethan kills Ambrose’s men but Ambrose chases him to a beach where Ethan defeats him in a brutal fistfight. With little time left on the 20-hour countdown, Luther reaches Ethan at the beach. As Ethan is about to give Luther the Bellerophon canister, Ambrose recovers and points a gun at Ethan. Ethan throws the canister to Luther and jumps away from Ambrose’s shot while kicking up a gun from the sand which he uses to finally kill Ambrose. Luther injects Nyah with the Bellerophon in time to cure her.
IMF clears Nyah’s criminal record and Ethan starts his vacation with her in Sydney.