Two years after Solomon Lane's capture at the hands of Ethan Hunt, the world is faced with unintended consequences. Despite the Syndicate's dissolution, remnants of the organization have formed a splinter faction calling themselves the "Apostles". Although they are still loyal to Lane and his cause, the Apostles now work as terrorists-for-hire, making them an even greater threat. Their latest employer is a mysterious extremist known only as "John Lark". It is believed that John Lark and the Apostles have unleashed a smallpox plague in Kashmir, and even though the virus is currently being contained, Lark has now hired the Apostles to steal three plutonium cores. When Ethan and his team are sent to Berlin to prevent the Apostles from escaping with the plutonium, the mission suddenly goes wrong when Luther is taken hostage, and Ethan saves Luther but lets the Apostles escape with the payload. Despite this, Ethan and his team capture scientist Nils Debruuk and learn that he built three portable nuclear weapons for the cores.
Following the IMF's failure to secure the plutonium, CIA director Erica Sloane sends in her top agent August Walker to monitor Hunt in the mission to retrieve the plutonium. Ethan and Walker travel to Paris on plane and arrive at a party, where it is believed that Lark is planning on buying the cores from a female arms dealer known as the White Widow, the daughter of Ethan's old adversary Max. The two pursue a man whom they suspect to be Lark in a bathroom and attempt to subdue him, but the man fights back until the man is shot and killed by Ilsa Faust. Ethan is then left but with no choice but to pose as Lark when meeting with the White Widow. Meanwhile, Walker passes evidence onto Sloane and suggests to her that Ethan was Lark all along, and that the man Ilsa killed was a decoy.
While meeting with the White Widow, Ethan is given an assignment to break Lane out of his custody in an armored convoy moving through Paris. As payment, she provides Ethan one of the three plutonium cores. Ethan and Walker then attack the convoy, freeing Lane, and leads the police and the White Widow's men on a massive chase through the streets of Paris. In the process, Ilsa appears and attacks Ethan, attempting to kill Lane to prove her loyalty to MI6. Ethan, however, manages to escape and deliver Lane to London.
At a safehouse in London, Ethan meets with IMF Secretary Alan Hunley, who confronts him about being John Lark. Ethan denies it and subdues Hunley, planning to continue the mission. When Walker is assigned to guard Lane, Walker talks with Lane, who unknowingly is actually Benji wearing a mask, and unintentionally reveals himself to be the real John Lark and partners with Lane. Sloane then sends in a CIA unit to extract Ethan and his team, only for the unit to be the Apostles in disguise, and under Walker's orders, attacks the team. After Walker kills Hunley, Ethan chases after Walker through London, who manages to escape in a helicopter with Lane but not before threatening to harm Julia should Ethan not turn himself in as John Lark.
Ethan and his team track down Walker and Lane to a medical camp in Kashmir, and they deduce that the two plan on detonating the weapons over the Siachen Glacier, thus contaminating the water supply for Pakistan, India, and China, and that with a third of the world's population affected, the old world order would soon crumble and a new one will rise. It also turns out that Walker and Lane had arranged for Julia and her new husband Patrick to be at the medical camp, therefore increasing pressure onto Ethan. After the nuclear weapons are activated, Walker escapes onto a helicopter with the detonator, and Lane chooses to stay behind, planning to die when the weapons go off and having become a suicidal nihilist after having been tortured and interrogated for two years. Ethan hijacks the second helicopter to prevent Walker from escaping, leaving Benji and Ilsa to find Lane and the second bomb, with Luther and Julia working on defusing the first bomb at the medical camp. Benji and Ilsa manage to locate the second bomb, subduing Lane in the process. After crashing their helicopters, Ethan and Walker fight over the detonator on the edge of a cliff and Walker is eventually killed when Ethan throws a winch at his face. Ethan then disables the detonator, allowing Luther, Benji, and Ilsa to safely defuse the bombs.
In the aftermath, Ethan rejoins his team and recovers from his injuries. The two plutonium cores are recovered, and sometime later, Ethan and Sloane hand over Lane to the White Widow, who will in turn hand him over to MI6.