Jim Phelps and his team, the Impossible Missions Force (IMF), attempt to retrieve the CIA non-official cover (NOC) list from the American embassy in Prague. Their mission fails: Phelps is shot, his wife Claire dies in a car bombing, and the rest of the team except Ethan Hunt are eliminated by unknown assassins and supposed tech malfunctions. Meeting with IMF director Eugene Kittridge, Hunt reveals his awareness of a second IMF team sent to monitor them, and learns the job was a setup to lure out a mole within the IMF, who is believed to be working with an arms dealer known as "Max" as part of "Job 314." As Hunt is the only member left, Kittridge suspects him of being the mole, and Hunt flees.

Returning to the Prague safe house, Hunt realizes "Job 314" refers to Bible verse Job 3:14, "Job" being the mole's code name. Claire arrives at the safe house, explaining she escaped the bomb after Phelps aborted the mission. Hunt arranges a meeting with Max, and warns her that the list she possesses has a tracking device. He promises to deliver the real list in return for $10 million and Job's identity. Hunt, Max, and her agents escape just as a CIA team arrives.

Hunt recruits two disavowed IMF agents: computer expert Luther Stickell and pilot Franz Krieger. They infiltrate CIA headquarters in Langley, steal the real list, and flee to London. Kittridge, detecting the theft, has Hunt's mother and uncle falsely arrested for drug trafficking. He provides media coverage of the arrest, forcing Hunt to contact him from Liverpool Street Station. Hunt allows the CIA to trace him to London before hanging up, but is surprised to find Phelps nearby. Phelps recounts surviving the shooting, naming Kittridge as the mole. Hunt realizes Phelps is the mole, as the Bible from the Prague safe house had a Gideon stamp from the Drake hotel in Chicago; the same hotel Phelps was staying at during a previous assignment, which was known to Hunt and the team. Hunt also suspects Krieger as the one who killed the other IMF members on the Prague job since Krieger carried a characteristic knife; however, he is unsure whether Claire was involved. Hunt arranges with Max to exchange the list aboard the TGV train to Paris the next day.

On the train, Hunt remotely directs Max to the list. Max verifies it and gives Hunt the code to a briefcase containing the payment along with Job in the baggage car. Ethan calls Claire and tells her to meet him there. Meanwhile, Stickell uses a jamming device to prevent Max from uploading the data to her servers. Claire reaches the baggage car, finds Phelps and tells him Ethan will arrive shortly. She questions the idea of killing Ethan, since they will need a fall guy, when Phelps reveals himself to be Ethan in a mask, exposing her as a co-conspirator. When the real Phelps arrives and takes the money at gunpoint, Hunt dons a pair of video glasses that relays Phelps to Kittridge, blowing Phelps' cover as the mole.

Phelps threatens to kill Ethan, but shoots Claire instead when she intervenes. He climbs to the roof of the train, where Krieger is waiting with a helicopter and a tether. Hunt connects the tether to the train itself, forcing the helicopter into the Channel Tunnel after the train. Hunt places an explosive chewing gum on the helicopter windshield, killing Krieger and Phelps. Kittridge arrests Max and recovers the list, then reinstates Hunt and Stickell as IMF agents, but Hunt is unsure if he will accept. As he flies home, a flight attendant approaches him and asks, through a coded phrase, if he is ready to take on a new mission, just as she asked Phelps at the beginning.