IMF agent Trevor Hanaway is killed in Budapest by assassin Sabine Moreau, who takes the file containing Russian nuclear launch codes he had stolen so she can give them to a man known only as "Cobalt".
Meanwhile, IMF agent Ethan Hunt has purposely become incarcerated into a Moscow prison to acquire Bogdan, a source of information on Cobalt.
With help of Jane Carter, Hanaway's handler, and newly promoted field agent Benji Dunn, Hunt and Bogdan make their escape. IMF tasks Hunt to infiltrate the Kremlin to gain more information on Cobalt.
During the mission, an unknown entity broadcasts on the IMF frequency ordering the detonation of a bomb. Hunt's team aborts the mission just as a bomb destroys much of the Kremlin.
Carter and Dunn escape, but Hunt is captured by SVRagent Anatoly Sidorov and charged with the destruction of the Kremlin.
Hunt is able to escape and regroups with the IMF Secretary who is in Moscow on other business.
The Secretary tells Hunt they have had to initiate "Ghost Protocol", disavowing IMF, but secretly orders Hunt to continue to pursue Cobalt. Sidorov's forces catch up to Hunt, and the Secretary is killed; Hunt escapes along with the Secretary's aide and intelligence analyst William Brandt. Regrouping with Carter and Dunn, Brandt is able to identify Cobalt as Kurt Hendricks, a Swedish-born Russian nuclear strategist, who seeks to start a nuclear war between the U.S. and Russia.
Hendricks used the Kremlin bombing to cover up his theft of a Russian nuclear launch-control device, and now is planning a trade with Moreau at the Burj Khalifa in Dubai to gain the required launch codes.
The team travels to Dubai. On the 119th floor of the hotel, they create deceptions using their various gadgetry and disguises to make Moreau believe she is meeting with Hendricks, and vice versa, when in fact they are interacting with the IMF team.
Moreau discovers the deception, and in the ensuing chaos, Hendricks manages to escape with the launch codes, losing Hunt's pursuit in the midst of a dust storm.
Carter knocks Moreau out of a window to her death when she tries to escape. Brandt accuses her of letting her love for Hanaway compromise the mission, but Hunt recognizes that Brandt has also been keeping secrets from them, having shown combat skills atypical of a mere analyst.
Hunt leaves to meet with Bogdan to get more information on Hendricks, while Brandt tells the others that he had been assigned to secretly protect Ethan and his wife Julia in Croatia.
Julia had been killed by a hit squad and Brandt feels responsible for Ethan's loss, which is why he stopped being a field agent.
Bogdan directs Ethan towards Mumbai, where Hendricks is set to negotiate with Indian telecommunications entrepreneur Brij Nath to gain control of an obsolete Soviet military satellite. The IMF team splits up to stop Hendricks; Carter seduces Nath to get the satellite override code, while Hunt, Brandt and Dunn try to stop Hendricks from using Nath's broadcast station.
They are too late as Hendricks has sent the launch codes to a Russian Delta III-class nuclear submarine to fire a single missile at San Francisco and disabled the station's computer systems.
Brandt and Dunn race to get the systems back online to send the override code, while Hunt pursues Hendricks, eventually fighting him face to face in an automated car park.
Hendricks, with the launch device, jumps to his death moments before the missile is set to land.
Hunt then uses one of the cars and takes a dangerous fall to use the device; he barely disables the missile before it strikes. Sidorov, who has followed IMF from Dubai to Mumbai, arrives and realizes that the IMF is innocent of the Kremlin bombing.
The team meets in Seattle after Ethan accepts a new mission from Luther Stickell. Brandt confesses to Ethan about his failure to protect Julia.
Ethan, however, reveals that her "death" and the murder of the Serbians were part of a plot to give her a new identity and enable Ethan to infiltrate the prison.
A relieved Brandt happily accepts his mission, and becomes an agent once again. Meanwhile, Julia arrives at the harbor.
Ethan and Julia gaze at each other from afar before Ethan departs for his next mission.
