Benji and new team member Jane Carter break Ethan out of a Russian prison, with even Benji not knowing why he's there beyond something to do with the end of his marriage to Julia. After Ethan complicates things by insisting on rescuing fellow prisoner Bogdan who'd been giving him information, they succeed and Jane explains one of her ops just went bad, with her handpicked agent Hanaway killed by assassin Sabine Moreaux while delivering Russian nuclear launch codes. Sabine typically works for a terrorist known only as Cobalt, so the team is sent to infiltrate the Kremlin to steal the launch devices before he can use them.
Ethan and Benji get into the Kremlin posing as Russian military, and get past the guard at the archive room using a screen projecting a perfect image of an empty hallway. However, the devices are already gone, and soon a strange voice appears on their radio frequency ordering a detonation. Ethan and Benji are forced to run, even going right past Cobalt, and as soon as Ethan gets outside the building is destroyed in a massive explosion.
Ethan wakes up in handcuffs in the hospital, and is confronted by SVR Agent Anatoly Sidorov who gloats about capturing him. Ethan steals a paper clip to pick the handcuffs and escapes the hospital by swinging down a clothesline, and calls headquarters to be picked up. When the car arrives, he's met by none other than the IMF's leader known only as the Secretary, plus his chief analyst William Brandt, who reveal the President has disavowed the entire IMF after they were blamed for the explosion. The Secretary has arranged for Ethan to escape and continue the mission, with Brandt identifying Cobalt as Kurt Hendricks, a Swedish nuclear strategist. But just then the car is attacked and the Secretary is killed, with Ethan and Brandt barely escaping when it crashes into a river.
Ethan and Brandt get to the train car base the Secretary arranged and find Benji and Jane already waiting. They also have new intel on Hendricks, who believes a worldwide nuclear war is necessary for humanity to evolve. The last piece of information is that Sabine is handing off the codes at the Burj Khalifa, so they create a plan to control the elevators to put Hendricks' henchman Marius Winstrom on the wrong floor, using masks to have Benji pose as Winstrom and Jane as Sabine while each meets with the other.
The plan hits a snag due to the Burj's top-notch electronic security, and without the IMF's resources the only way to hack into the elevators is for Ethan to scale the outside of the building to the server room using electronically adhesive gloves. Despite some issues with the gloves shorting out, he's able to finish the hack and barely gets back down to the team's room. But that's far from the end of the problems, as Winstrom brings along nuclear technician Leonid Lisenker to verify the codes after kidnapping his family, stopping the plan to just give them fake codes. The mask machine also malfunctions and forces the team to go without them, though luckily it turns out Winstrom and Sabine have never met. Benji poses as a bellhop to transfer Sabine's diamond payment between the two meetings, and everything is about to conclude when Sabine spots the contact lens Brandt is using to copy the codes to the other meeting. In the ensuing fight Brandt displays combat skills that make clear he's not just an analyst, and Jane heads after Sabine, ultimately kicking her out a window to her death. Ethan has to deal with interference from Sidorov and a sandstorm while chasing Winstrom, and ultimately loses him while discovering it was actually Hendricks himself under another mask.
As the team berates each other over Hendricks now having the real launch codes, Ethan heads out to a meeting after taking a mysterious phone call. With him gone, Brandt tells the others that he indeed was a field agent, but left after he failed to save Julia from a Serbian hit squad, which led to Ethan killing them all in revenge until he ended up in prison as seen before. He's still struggling with how to tell Ethan it was him.
Ethan's meeting turns out to be with Max's old Henchman, who brings him to meet Bogdan's cousin known as The Fog, an arms dealer who knows everything they need to stop Hendricks. He sends the team to Mumbai where art collector Brij Nath's servers can be used to stop the missile, but then calls Sidorov with the location. Jane seduces Nath to get the server codes, while Brandt has to brave the superheated server room using a magnetic suit to suspend him in midair. Right after they get in, Hendricks stops the plan by crashing the server from a TV station's array, forcing the team to race over there. Ethan pursues Hendricks again while Winstrom is left behind to stop the others from accessing the system, and is ultimately shot by Benji. Ethan's final showdown with Hendricks takes place in a car factory, where Hendricks makes a suicidal jump to stop Ethan from using his control panel for the missile. Ethan has to drive a car down after him where he's saved by the airbags, and the missile is aborted with seconds to spare. Sidorov arrives, and it turns out Ethan actually told The Fog to call him, so he could see the truth for himself.
Ethan meets with Luther, who's been leading the search for the aborted missile, and introduces him to the new team. He offers for them all to become a permanent unit, but Brandt demurs and admits his failure to save Julia. However, Ethan reveals that the mission was actually a setup to get him to Hendricks' contacts in the prison, as well as faking Julia's death as the only way to ensure her safety. With his guilt lifted, Brandt is now on board, and Ethan shares a longing look with Julia before getting a call about a dangerous new criminal organization known as the Syndicate.
