Dr. Vladimir Nekhorvich sends a message to Ethan, who he knows from a previous IMF mission, to get him to America within twenty hours due to a mysterious substance called Chimera. Ethan meets him on the plane, and after confirming Nekhorvich is also carrying Chimera's opposite substance Bellerophon, kills him with a chop to the throat. It turns out this isn't Ethan but another man using IMF's mask tech, and with a few team members he escapes with Nekhorvich's case before crashing the plane.
The real Ethan is on vacation free climbing (at Dead Horse Point, Utah) when he's contacted by his new superior Swanbeck about Chimera, and instructed to first recruit the civilian Nyah Nordoff-Hall in Seville before being briefed on the rest of the mission. Nyah turns out to be a cat burglar, and Ethan interferes with her theft of a necklace, followed by a car chase on precarious mountain roads. After he saves Nyah from falling over the edge, she finally agrees to go on the mission and they even sleep together.
Ethan meets up with Swanbeck, who reveals the man who stole Chimera is another IMF agent, Sean Ambrose, who was sent on the job when they couldn't get hold of Ethan in time only to go rogue. Nyah was previously in a relationship with him and he's been obsessed with her ever since, so now she's the ideal way to get close to him, despite both she and Ethan being opposed to the job. IMF arranges for her to be arrested so Ambrose will break her out, while Ethan brings back Luther plus replacement pilot Billy Baird for the rest of the job.
Nyah's entrance to Ambrose's estate in Sydney goes off without a hitch, though Ambrose's henchman Hugh Stamp is suspicious of her. Ambrose responds that he knows full well how suspicious the timing is, and is so insulted Stamp would think he could be fooled so easily that he cuts off the tip of Stamp's finger with a cigar slicer.
Ambrose takes Nyah to a horse race, where the team spots him showing a video to Nekhorvich's boss John McCloy. Nyah easily lifts the video card from Ambrose's jacket while Billy distracts Stamp long enough for her to pass it to Ethan. The video reveals that Chimera is a virus that becomes invariably fatal after twenty hours, and Ethan declares Nyah should leave that very night. But even that becomes too late when Ambrose notices she put the video card back into the wrong jacket pocket, and he approaches her disguised as Ethan which confirms her true loyalty.
The team kidnaps McCloy and Ethan poses as Nekhorvich, which gets McCloy to reveal he bankrolled the creation of Chimera to make a superbug whose cure Bellerophon he would hold a monopoly on, only for Nekhorvich to inject himself with it trying to smuggle it to IMF so they could stop the scheme. Ethan sets out to break into the company to destroy all the remaining Chimera, but Ambrose knows every step of what he'll do, and interrupts him with a team of soldiers just before he finishes the job. Ethan can't defeat them all, so Nyah takes matters into her own hands and injects herself with the final dose, to which Ethan can only make his own escape with twenty hours to save her.
After tracking McCloy to the lab where he'll be buying Chimera back, Ethan makes quick work of several guards until Stamp is sent out after him. After their own fight, Stamp comes back in dragging Ethan, who he says can't talk due to a broken jaw. Ambrose tortures him and finally shoots him dead, but then notices his bandaged finger, revealed that Ethan won the fight and then gagged Stamp before using more masks to switch places with him. While everyone was distracted, he also escaped with Bellerophon, leading to a massive chase and then fight between the two equally trained agents. Finally, Ethan ends up the winner and guns Ambrose down, and Nyah is retrieved to be injected with Bellerophon.
Swanbeck debriefs Ethan, disappointed at his not bringing any Chimera back to be in American hands but agreeing to completely clean out Nyah's criminal record after the mission's success. Ethan heads out on vacation again and goes back to Sydney, where he meets Nyah again.
