NSA Agent Augustus Gibbons attempts to recruit footballer Neymar Jr. for the xXx program when a satellite crashes in Brazil, apparently killing them both. Shortly afterwards, a team of four skilled individuals led by Xiang infiltrates a highly guarded CIA office in New York City and retrieve "Pandora's Box", a device which is capable of controlling satellites to crash at specific locations as warheads. CIA Agent Jane Marke tracks down former xXx operative Xander Cage, who faked his death and has been living in self-imposed exile in the Dominican Republic, and convinces him to return to active service to retrieve the device.

After enlisting an old friend, Ainsley, for help, Cage tracks down the attackers to the Philippines. A unit of Special Forces operatives led by Paul Donovan is assigned to help Xander, but he rejects them in favour of his own team, composed of sharpshooter Adele Wolff, DJ Harvard "Nicks" Zhou, and getaway driver Tennyson "The Torch." They are also aided by introverted weapons specialist Becky Clearidge. The team locates Xiang and his teammates Serena, Talon and Hawk, and Cage meets Xiang in an underground nightclub on a remote island, where Xiang reveals that his team are all part of the xXx program, recruited by Gibbons. He claims to have stolen Pandora's Box to prevent its misuse, although Serena believes they should destroy it.

Shortly after, Russian soldiers raid the island. The group manages to fend off the attackers, while Xiang manages to escape with Pandora's Box. Xander intercepts Xiang and chases him to a nearby beach. Serena betrays him, destroys the Box and joins Xander's team, while Xiang escapes and regroups with Talon & Hawk. After another satellite crash in Russia, Marke determines that the device that Serena destroyed was only a prototype, and that both teams have been wasting time, while Cage determines that CIA Director Anderson is involved in the conspiracy and that the actual Pandora's Box is in his hands.

Cage's and Xiang's teams race to reach Anderson first in Detroit, tracking the unique signal of Pandora's Box, with Xander and Xiang fighting and later protecting each other from Anderson's men. Xander confronts Anderson, who admits to causing the satellite crash that killed Gibbons. Anderson is then shot dead by Wolff. The CIA arrests Xiang in an attempt to frame him for the attack in Russia, and secures the box. En route back to headquarters, Marke announces that the xXx Program has been shut down and shoots Xander in order to keep it for herself. She then sends a group of assassins to eliminate the others, who are awaiting extraction at a local NSA warehouse. They join forces to fend off their attackers and receive assistance from another former xXx operative, Darius Stone.

Xander survives due to a bulletproof vest Becky had given him earlier and joins forces with Xiang to fight Donovan and his men, while Marke uses the box to send a satellite plummeting towards the warehouse where the teams are fighting. Xander ejects Donovan from the plane, while Xiang sends Marke falling to her death and then parachutes out with the box in hand. Despite Becky's attempts to halt the signal, they cannot stop the satellite from crashing. In a last attempt to protect them, Xander crashes the plane into the approaching satellite before it reaches the warehouse and jumps out, using the cargo load to safely reach the ground. Xiang gives Cage the device, and Xander decides to destroy it. The team attends Gibbons' funeral, where Xander is approached by Gibbons himself, who faked his death and is now rebuilding the xXx Program on his own, starting with Neymar as the newest recruit. Gibbons compliments Xander on a job well done and Xander decides to continue in service, ready for a new mission to watch the watchers and preserve liberty.

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