The film opens as Ethan Hunt (Tom Cruise) listens to a classified message from Erika Sloane (Angela Basset), who is now President of the United States. Gabriel (Esai Morales) and The Entity remain at large, as The Entity has now corrupted cyberspace and manipulated information to turn mankind against one another. A doomsday cult around The Entity has even been inspired. The only way to stop The Entity is to find its original source code and pair it with the cruciform key that Ethan has managed to keep from Gabriel. Ethan fears that if the government got their hands on The Entity, they may use it against other nations. Sloane tells Ethan that killing The Entity would completely wipe out all of cyberspace, plunging the world into another war. She pleads with Ethan to surrender before the message self-destructs.
Ethan reunites with Benji (Simon Pegg) and Luther (Ving Rhames) before going to an Austrian prison to break out Gabriel former accomplice, Paris (Pom Klementieff). She is being escorted by Agents Jasper Briggs (Shea Whigham) and Theo Degas (Greg Tarzan Davis), until Ethan and Benji infiltrate the prison. They briefly scuffle with the two agents until Ethan convinces Jasper and Degas to let them take her for the sake of stopping The Entity.
The team goes to the U.S. Embassy in London. Two other agents spot Ethan and prepare to turn him in, until Grace (Hayley Atwell) shows up and pickpockets their items, forcing them to let him go. She tells Ethan that she was sent to find him by Kittridge (Henry Czerny). Suddenly, a pair of Gabriel goons show up and tranquilize the two.
Ethan and Grace wake up with their hands tied and are met by Gabriel. He brings up Ethan mission in acquiring the Rabbit Foot (from the third movie) and how it was essentially an early copy of The Entity, and Ethan basically handed to the U.S. government. Ethan and Grace know that The Entity has forsaken Gabriel due to his previous failure in getting the key. Gabriel orders Ethan to find the Rabbit Foot from the sunken Sevastopol submarine. Ethan then produces a cyanide cap since he knows Gabriel needs him alive. After biting down onto it, Ethan starts to foam at the mouth, and Gabriel orders his goons to revive him as he slips away. Once freed, Ethan beats up the goons and kills them before freeing Grace and fleeing.
Ethan and Grace run into Benji, Paris, and Degas. They come upon a large device that Gabriel uses to communicate with The Entity. Ethan gets inside and connects himself so that he may also talk to the AI. The Entity knows that Ethan plans to destroy it using a "Poison Pill" that Luther developed and connecting it with The Entity core module, or the "Podkova". It shows Ethan visions of nuclear war and wants Ethan to help bring it to The Doomsday Vault in South Africa, which has a server room where it may survive.
Ethan splits from the team so they can retrieve the coordinates to the Sevastopol location. He races on foot to go find Luther, as he knows Gabriel is targeting him since he warned Ethan that someone close to him would die. Gabriel has taken Luther from the hospital where he was at and has placed him underground with a bomb, along with stealing the Poison Pill. If it goes off, it can take out the entire city, but Luther tries to limit its proximity. Ethan and Luther share a final moment before Ethan runs, and Luther is taken out in the ensuing explosion. Out on the streets, Jasper finds Ethan, and he surrenders himself and the key to Jasper.
Onboard a plane back to the U.S., Ethan reveals he has know that Jasper real name is Jim Phelps, Jr, making him the son of Ethan former mentor and IMF agent who betrayed him and the rest of his team before Ethan killed him. While Ethan knows that The Entity wants to turn Jasper against him, Jasper suggests that when all is said and done, they will deal with each other.
Ethan is met by Kittridge, who informs him that The Entity has already begun breaking into several nuclear arsenals around the world, with only a few left that are still secure. Ethan is brought to meet with the Joint Chiefs of Staff, including General Sydney (Nick Offerman). They review Ethan infamous exploits, such as his breaking into a CIA vault (from the first movie) and outrunning the Kremlin bombing (from the fourth). Sloane arrives, telling Ethan she wants him to help them control The Entity, but he does not trust any one person to handle a weapon like that. Ethan convinces her to allow him to work alone in locating the Sevastopol, or else a full-scale nuclear attack within 72 hours will go off.
Ethan is taken to a carrier in the Northern Pacific to meet with Admiral Neely (Hannah Waddingham). He hands her an envelope given to him by Sloane, with the date "May 22, 1996" written on it. Neely knows it is because both her and Sloane served in Siberia on that date and lost someone close to them. She reluctantly helps Ethan arrive at the Bering Sea, where the IMF team will meet him above the ice caps at a very specific time and place.
Benji, Grace, Paris, and Degas arrive on St. Matthew Island to the home of William Donloe (Rolf Saxon), who originally worked at the CIA and was transferred there after Ethan vault break-in. Donloe lives with his wife, Tapeesa (Lucy Tulugarjuk). Despite trying to maintain a cover, Benji cannot help but geek out when he meets Donloe, forcing Grace to come clean about why they have come seeking him. Donloe knows of the Sevastopol coordinates, though he realizes they are dealing with The Entity. Making matters more complicated are a team of Russian mercenaries that are already in Donloe house, as they are also looking for the Sevastopol. The team helps fight back against the Russians in a gunfight, but Donloe house burns down. They manage to get him and Tapeesa out of there.
Ethan is dropped off into the Bering Sea and meets with a team led by Captain Bledsoe (Tramell Tillman). As he is preparing himself to dive underwater, one member of the team, Hagar (Tomas Paredes), is revealed to be an acolyte of The Entity and tries to kill Ethan. They fight until Hagar is knocked out by another team member, Kodiak (Katy O Brian).
The sub team arrives at the coordinates, dropping Ethan off into the waters with a suit of their own. He makes it inside the Sevastopol and finds the bodies of crew members who were not sucked out of the sub when it was hit. Ethan manages to find the Podkova, but he has tilted the sub, which has started to sink further down the continental shift. Ethan tears off his suit in order to get out, but he starts to drown as he hits the ice caps, right where the team was stated to find him. He is pulled out of the water by Grace.
After being revived in a decompression chamber, Ethan rejoins the team. He speaks to Donloe and is apologetic about being the reason he was relocated to the Arctic, but Donloe says he has no regrets since that is where he met Tapeesa. The team then discusses their plan to upload The Entity to a physical drive after connecting the Poison Pill to the Podkova, but the tricky part is doing it at the right time, not a moment too early or too late. Ethan anticipates that Gabriel is already at the Doomsday Vault and that he is waiting for them to surrender the Podkova to him so that he may control The Entity. Ethan also entrusts Grace with the job of doing the upload.
Back in the U.S., Sloane and her Cabinet are discussing contingency plans, as The Entity is targeting several major cities. They suggest one alternative is to deliberately nuke a city of Sloane choosing to spare the lives of billions. After Sloane picks a city, she prepares to launch the nuke until she makes the decision to take all American nukes offline to prevent The Entity from gaining any access into their arsenal. Another secret acolyte tries to shoot Sloane, but Sydney takes the shot and kills the acolyte himself before succumbing to his wound. The rest of the Cabinet complies with Sloane orders.
The team makes it down to the Vault, where they are met by Gabriel, along with Jasper and Kittridge. In the middle of the area is a large nuclear device that Gabriel has triggered to go off within 20 minutes. Kittridge wants to take the Poison Pill and Podkova so that the U.S. can control The Entity, but a gunfight breaks out, leaving Gabriel room to escape with the Poison Pill. Ethan goes after him while Benji, Grace, and Paris make it into the server room to complete the upload. Benji gets shot and requires an impromptu surgery from Paris, who manages to save him as he guides Grace through the process of performing the upload. Donloe, Tapeesa, and Degas stay behind to disarm the nuke.
Gabriel gets away in a biplane, but Ethan latches himself onto another passing plane. After taking out the pilot (who was...hopefully a bad guy), Ethan chases Gabriel and gets into a dogfight with him. After a while, Gabriel manages to cause Ethan is plane to fail, so Ethan jumps onto Gabriel plane. He knocks Gabriel out and takes the Poison Pill. Ethan loosens Gabriel seat belt, leaving him hanging. Gabriel brags and laughs about being the only one with a parachute before letting go...and promptly hitting the planes rudder groin-first, then smashing his skull against it, and finally plummeting to the ground below. Ethan tries to deploy another parachute, but it burns up in the air. Ethan continues falling but manages to connect the Poison Pill and Podkova. Grace manages to complete the upload at just the right time, finally trapping The Entity for good. Donloe, Tapeesa, and Degas manage to disarm the bomb and escape the explosion in time.
Ethan is saved by a backup parachute. The Poison Pill then plays a final message from Luther, who knew that Ethan would do what it took to save the world. He repeats the IMF oath - "We live and die in the shadows, for those we hold close, and those we never meet." - and gives Ethan a final goodbye. Ethan is found by Kittridge and Jasper. Kittridge is annoyed at seeing the fried Podkova, but Jasper appears to have forgiven Ethan for what happened with his father, and they part on good terms.
The IMF team meets in London, all at a distance from each other. Grace approaches Ethan to give him The Entity in its drive. Ethan shares looks with Benji, Paris, and Grace one more time before they go their separate ways, into the shadows once more.
