During a mission in Budapest to intercept a courier working for a person code-named "Cobalt", IMF agent Trevor Hanaway is killed by assassin Sabine Moreau. Hanaway's team leader, Jane Carter, and newly promoted field agent Benji Dunn extract Ethan Hunt and Ethan's source, Bogdan, from a Moscow prison. Ethan is recruited to lead Jane and Benji to infiltrate secret Moscow Kremlin archives and locate files identifying Cobalt. During the mission, someone broadcasts across the IMF frequency, alerting the Russians to Ethan's team. Although Benji and Jane escape, a bomb destroys the Kremlin and SVR agent Anatoly Sidorov arrests Ethan, suspecting him as a key player in the attack.
The IMF extracts Ethan from Moscow. Russia considers the attack an undeclared act of war, and the U.S. President activates "Ghost Protocol", a black operation contingency that disavows the IMF. Ethan and his team are to take the blame for the attack but will be allowed to escape from government custody in order to track down Cobalt. Before Ethan can escape, the IMF Secretary is killed by Russian security forces led by Sidorov, leaving Hunt and intelligence analyst William Brandt to find their own way out. Brandt identifies Cobalt as Kurt Hendricks, a Swedish-born Russian nuclear strategist who plans to start a nuclear war. Hendricks bombed the Kremlin in order to acquire a Russian nuclear launch-control device; however, he now needs the activation codes from the Budapest courier in order to launch nuclear missiles at the United States.
The exchange between Moreau and Hendricks' right-hand man, Wistrom, is due to take place at the Burj Khalifa in Dubai. There, Ethan's team members separately convince Moreau and Hendricks' right-hand-man, Wistrom, that they have made the exchange with one another. However, Moreau identifies Brandt as an agent. While Ethan chases Wistrom—only to realize that Wistrom is actually Hendricks in disguise, escaping with the codes—Jane detains Moreau. Moreau attempts to kill the inexperienced Benji, and Jane kicks her out a window to her death. Brandt accuses Jane of compromising the mission for revenge against Moreau, but Ethan accuses Brandt of keeping secrets from them, as he has demonstrated skills decidedly atypical of a mere analyst. While Ethan seeks more information from Bogdan, Brandt confides to Benji and Jane that he was assigned as security detail to Ethan and his wife Julia while they were on vacation in Croatia. While Brandt was on patrol, Julia was killed by a Serbian hit squad, prompting Ethan to pursue and kill them before he was caught by the Russians and sent to prison.
Bogdan and his arms-dealer cousin inform Ethan that Hendricks will be in Mumbai. The arms dealer facilitated the sale of a defunct Soviet military satellite to Indian telecommunications entrepreneur Brij Nath. The satellite could be used to transmit the launch codes for nuclear-tipped missiles. While Brandt and Benji infiltrate the server room to deactivate the satellite, Carter gets Nath to reveal the satellite override code. But Hendricks has anticipated Ethan's plan and infects Nath's servers with a virus before sending a signal from a television broadcasting tower to a Russian ballistic missile submarine in the Pacific to fire at San Francisco. Ethan pursues Hendricks and the launch device while the other team-members attempt to bring the broadcast station back online. Ethan and Hendricks fight over the launch-control device before Hendricks jumps to his death with it to ensure success. Benji kills Wistrom, allowing Brandt to restore power to the station and enabling Ethan to deactivate the missile, while the fatally wounded Hendricks witnesses the failure of his plan as he dies. Sidorov happens upon the scene in time to see what Ethan has done and realizes that the IMF is innocent of bombing the Kremlin.
The team reconvenes weeks later in Seattle with Ethan meeting up with Luther Stickell and accepting a new mission. He asks Benji, Carter, and Brandt to be his team. Benji and Carter accept and walk away. Brandt refuses at first and confesses to Ethan about being assigned to protect Julia and failing. However, Ethan reveals that Julia was kidnapped but not killed and the death of the Serbians occurred during her recovery. Julia's death was then faked to keep her safe and Ethan's prosecution for the Serbian deaths was used as a way for him to infiltrate the Moscow prison, where the Secretary believed Cobalt had contacts. Ethan goes on to tell Brandt that it was Ethan's job to keep Julia safe, not Brandt's. A relieved Brandt then accepts the mission. Julia is shown alive and smiles at Ethan from across the port. Following Julia's departure, Ethan is contacted with another mission, then vanishes into the fog.....