Impossible Missions Force Agent William Brandt (Jeremy Renner) is directing two members of his team, Benji Dunn (Simon Pegg) and Luther Stickell (Ving Rhames), in an attempt to retrieve a package from a cargo plane that's about to take off in Minsk, Belarus. Luther is connecting Benji to the plane's electronics by hacking a Russian satellite, which is likely to get them into trouble -- and Brandt reminds them that they're already under investigation for misconduct. As the plane rolls onto the runway, Benji finds that most of the plane's systems are secured -- he can't shut down the fuel pump, the electrical system, or the hydraulics. Just then the missing member of the team, IMF Agent Ethan Hunt (Tom Cruise), sprints over a hill by the runway and leaps onto the plane, demanding that Benji open the plane's door. By the time Benji gets the right door open the plane is up and away, but Ethan escapes with the package -- many canisters of toxic nerve gas, conveniently prepared for a parachute drop.
The nerve gas was being sold to a terrorist group, but none of the people who sent it from Belarus had the means to obtain it. Ethan is convinced this trail will lead him to the Syndicate, an international criminal consortium whose very existence has been in doubt. Reporting to an IMF substation that's disguised as a London record shop to receive his next orders, Ethan is captured by the Syndicate and watches in horror as a Syndicate agent kills his contact. He wakes up in a torture chamber, where he observes some discord -- Syndicate operative and disavowed MI6 agent Ilsa Faust (Rebecca Ferguson), who's preparing to interrogate Ethan with drugs, is forced to step aside by her colleague Janik Vinter (Jens Hultén). He's called the Bonedoctor and has a case full of scary instruments to prove his right to the nickname. Ethan escapes with help from Ilsa, but she refuses to go with him.
Meanwhile, Brant appears with CIA director Alan Hunley (Alec Baldwin) before a Senate oversight committee. Brandt must respond to every question by refusing to confirm or deny anything without permission from the secretary (of defense, presumably) ... which he cannot get because there is, at the moment, no secretary in office. This allows Hunley to have his way with the committee. At his request the IMF is disbanded and absorbed into the CIA, guaranteeing that Ethan -- who Hunley thinks has gone rogue -- will be captured within the day.
Six months later, Ethan is still on the run. Unable to find the Syndicate without help, he enlists his former colleague Benji, who's happy to take a break from the CIA -- Hunley is sure Benji knows how to find Ethan and subjects him to weekly polygraphs (which Benji beats handily). Ethan arranges for Benji to attend Turandot in Vienna to search for Solomon Lane (Sean Harris), who Ethan suspects is the leader of the Syndicate. Although Ethan and Benji thwart three snipers at the opera (one of whom is Ilsa), the Austrian chancellor (Rupert Wickham) is killed by a car bomb. Ethan reveals to Benji that the Syndicate has been assassinating minor world leaders for some time; the murder of the chancellor of Austria is an escalation and a signal that the Syndicate is stepping out of the shadows.
Brandt recruits Luther to help find Ethan and prevent Hunley's team from killing him. Using a likeness of Ilsa left by Ethan, Brandt and Luther are able to track Ethan, Benji, and Faust to Morocco, where they're infiltrating a secure server underneath a power station. Their target is a well-protected ledger containing the names of all Syndicate agents and information on where the Syndicate keeps its money. The three of them execute an elaborate scheme in which Ethan is nearly drowned. As soon as he starts breathing again, Ilsa whacks Benji and takes the drive holding the ledger. During the ensuing chase, Brandt and Luther catch up with Ethan and Benji, while Ilsa joins a team of Syndicate motorcycle goons just long enough to get a bike of her own. Ilsa manages to escape, but Benji reveals he had already made a copy of the data.
Ilsa returns to London and attempts to pass the drive containing the Syndicate ledger to her handler, MI6 Director Attlee (Simon McBurney), who compels Ilsa to return to the Syndicate and finish her mission. She returns to Lane, only to find that Attlee has wiped the drive, which in fact contained an encrypted "red box." A red box is a data safe programmed by the British government; unlocking it requires the prime minister's biometrics. The former IMF agents confront Ilsa, but when Lane's men abduct Benji, Ethan and company are told they must deliver a decrypted copy of the drive to Lane.
Brandt contacts Hunley and reveals their location. At a charity auction, the two try and prevent Ethan from attacking the prime minister, whom they and Attlee take to a secure room. Ethan, having posed as Attlee, reveals himself and has the prime minister confirm the existence of the Syndicate, a classified project to perform missions without oversight (though the prime minister insists that he cancelled the project while it was still in the planning stages). When the real Attlee arrives, Ethan subdues him and he admits that he had been covering up the existence of the Syndicate since Lane hijacked the project and went rogue.
Luther discovers the file actually contains access to billions of pounds. Ethan memorizes the data and destroys the file to force Lane to release Benji and Ilsa in exchange for what he knows. He goads Lane, drawing him into the open and luring him into a bulletproof cell where he is taken into custody. Ilsa drives away, telling Ethan, "you know how to find me."
Some time later, Hunley and Brandt return to the oversight committee, where Brandt once again refuses to confirm or deny anything without permission from the secretary. Hunley secures the reinstatement of the IMF, claiming that his previous efforts to have it disbanded were all to allow Hunt to go undercover. The committee, though skeptical, approves, and on the way out Brandt addresses Hunley as "Mr. Secretary."