Two years after anarchist Solomon Lane's capture, the remnants of his organization of rogue clandestine operatives, the Syndicate, continue to wreak havoc around the globe and have reorganized as a terrorist group known as the Apostles. They are allied with a mysterious extremist known as John Lark, who wrote a manifesto calling for the destruction of the current world order.
At a safe house in Belfast, IMF agent Ethan Hunt is assigned to buy three stolen plutonium cores in Berlin from Eastern European gangsters, before the Apostles can. He is joined by Benji Dunn and Luther Stickell for the mission, but the team fails when Stickell is captured. Hunt's attempt to save Stickell allows agents of the arms dealer Alanna Mitsopolis (aka the White Widow) to seize the plutonium. The IMF team later captures nuclear weapons expert Nils Delbruuk, whose security clearance was revoked due to his anti-religious bigotry, and who designed nuclear bombs for the Apostles. Delbruuk explains the Apostles' credo that "there has never been great peace without first a great suffering. The greater the suffering, the greater the peace." Using a fake broadcast of Dunn posing as CNN's Wolf Blitzer, they trick Delbruuk into unlocking a phone that he used to communicate with Lark.
Furious at the IMF's failure to secure the plutonium, CIA Director Erika Sloane instructs Special Activities Division operative August Walker to shadow Hunt as he attempts to retrieve it. Hunt and Walker infiltrate a nightclub party in Paris where Lark is believed to be buying the cores from Mitsopolis, who is acting as the middleman in the sale of the plutonium. They track a man whom they suspect to be Lark, but after fighting him in a restroom, the man is killed by MI6 agent Ilsa Faust. Hunt assumes the role of Lark without a disguise and escapes from hitmen sent to kill both Lark and Mitsopolis.
In exchange for the plutonium, Mitsopolis tasks Hunt with extracting Lane from an armored convoy moving through Paris. She provides one of the plutonium cores as a down payment. To prevent Mitsopolis and her brother Zola from killing local police, Hunt and Walker preemptively attack the convoy. Ramming Lane's vehicle into water, they lead police and Mitsopolis's men on a chase across Paris while Dunn and Stickell, in a watercraft, secure Lane. Faust reappears and attempts to kill Lane to prove her loyalty to MI6, but the extraction is successful. Mitsopolis instructs Hunt to deliver both Lane and Faust to London.
At a London safe house, IMF Secretary Alan Hunley reveals evidence doctored by Walker and passed to Sloane, stating Hunt is the real Lark. Eventually, Hunt, the team, and Hunley trick Walker into admitting he is the real Lark and inform Sloane, who sends in a CIA unit to take everyone into custody for transfer to Washington, D.C. However, the CIA unit had been infiltrated by the Apostles, and Walker orders the infiltrators to attack, killing every other operator in the CIA unit. Walker kills Hunley and escapes after Hunt chases him across London. As he departs for India with Lane, Walker instructs Hunt to turn himself in and admit that he is Lark or else Hunt's ex-wife Julia will be harmed.
The team deduces that Lane and Walker plan to detonate the remaining two nuclear bombs at a medical camp over the Siachen Glacier, contaminating the water supply of India, Pakistan, and China; with a third of its population affected, the world will descend into an anarchy from which the Apostles hope a new world order will emerge. As the bombs are linked by a failsafe, any attempt to defuse one bomb without the detonator automatically triggers the other.
Upon arrival in Kashmir, Hunt discovers Julia and her new husband Erik are assigned to the medical camp, an arrangement made by Walker to increase the pressure on Hunt. Lane programs the bombs' detonator with a 15-minute countdown and gives it to Walker, choosing to remain behind with the bombs. Walker takes off, secretly pursued by Hunt while Dunn, Stickell, and Faust try to find and defuse the nuclear weapons. Stickell attempts to deactivate the first bomb with Julia's help, but they are unable to without the detonator. Faust and Dunn find the second bomb and are ambushed by Lane and subdue him after an intense fight. Following an aerial chase, Hunt uses a commandeered helicopter to ram Walker's helicopter out of the sky. After a fight on a cliff, Walker is killed. Hunt then secures the detonator, allowing the team to deactivate the nukes.
In the aftermath, Sloane hands Lane over to MI6 through Mitsopolis, with Faust earning her exoneration. Julia tells Hunt that he has given her the best life, despite his commitment to the IMF. Faust and the team join Hunt in celebration.