Ethan and his new wife Julia have been captured by arms dealer Owen Davian, who says he's put a bomb in Ethan's head before threatening to kill Julia unless he reveals the location of the "Rabbit's Foot." Ethan does his best to talk his way out of it, but Davian still ends up pulling the trigger.
Days earlier, Ethan and Julia host their engagement party, Ethan having retired from field work to become an instructor at IMF. However, he's pulled away by his replacement agent John Musgrave who reveals that Lindsey Farris, a trainee he'd grown especially close to, has been abducted by Davian while surveilling him. He's invited on the team to rescue her, which once again includes Luther, plus new members Zhen Lei and Declan Gormley.
The rescue itself goes off well, with the building's electricity cut off and drone guns confusing Davian's men while Ethan grabs Lindsey and Zhen gets their laptops, and they all get into Declan's helicopter. Along the way, Lindsey says she needs to tell Ethan something in private, but unfortunately they discover a bomb planted in her head, and despite Ethan's best efforts he isn't able to charge a defibrillator in time to fry it, and she's killed.
Back at IMF headquarters, Ethan and Musgrave are both chewed out by Director Theodore Brassel for the mission's failure. Shortly afterward, Ethan receives a postcard Lindsay sent just before her capture, with a hidden microdot which strangely doesn't seem to have any information. He gives it to tech expert Benji Dunn to investigate, who's also found information on the laptops about a meeting Davian is about to have at the Vatican about the Rabbit's Foot. Before heading back out, Ethan gets a priest at the hospital where Julia works to marry them.
Ethan breaks into the Vatican posing as a priest, while Declan dresses as a tourist and a guard and Zhen is a wealthy guest. Together they get images of Davian's face to make a mask for Ethan, and also get the briefcase he brought before they covertly enter the sewer from Zhen's car before blowing it up, seemingly killing the real Davian while they've actually captured him alive, with even his Head of Security being totally fooled. However, he refuses to give any information on his buyer or even what the Rabbit's Foot is, and just promises horrible revenge on both Ethan and Julia.
Upon landing in America, Davian is put in a prison van and Benji sends a video he found in the microdot, where Lindsey says she traced a call Davian made back to Brassel, who she now suspects set her up. Just then, the convoy is attacked by helicopters and the team is so busy protecting the civilians on the road that Davian gets away. His men quickly kidnap Julia, and Davian calls Ethan and demands he follow the instructions in the briefcase to deliver the Rabbit's Foot in 48 hours.
Before he can even start, IMF agents take Ethan into custody and Brassel gives an intimidating speech about how he won't tolerate loose cannons. Musgrave is then able to silently communicate that he intercepted Davian's call, and gives Ethan an apartment address in Shanghai before helping him escape. Shortly after Ethan gets there, the rest of the team arrives and sets up a heist that Luther calls even harder than the one to get the NOC list.
The heist requires entering through a skyscraper roof by swinging from a neighboring rooftop, followed by a dangerously low parachute jump after getting the Rabbit's Foot. Ethan is saved when his parachute catches on a light pole, and he calls Musgrave as he puts a tracker in the container. From there Davian directs him to get into a limousine where he's forced to drink a sedative, leading back to the opening scene.
Davian shoots Julia as seen before, after which Ethan is shocked to see Musgrave enter the room and reveal it was actually Davian's Head of Security in another mask, executed for her failure at the Vatican. The whole setup was a test to see if he'd really brought them the Rabbit's Foot, and Musgrave demands to know if his frame job on Brassel worked. Ethan manipulates him into calling the real Julia which gets him close enough to attack, and during his escape he calls Benji to track the phone.
After a mad dash through the city to get to Julia's location, Davian activates the bomb in Ethan's head, leaving him in agony. He pushes through the pain and tackles Davian out into the street where he's ignominiously killed by a car, after which Ethan desperately instructs Julia in how to disable the bomb and defend herself before using CPR to wake him back up. She manages to kill the remaining henchmen who come after them, including Musgrave, and successfully revives Ethan, leading him to tell her the whole truth about the IMF.
Brassel congratulates Ethan on a job well done and even says the President is looking at him for another job. Ethan, however, simply leaves for his honeymoon, not even curious about what the Rabbit's Foot really is.
