After two years of fighting organized crime as Deadpool, Wade Wilson fails to eliminate a target on his anniversary with his girlfriend, Vanessa. That night, the target tracks Wade down and accidentally kills Vanessa. Wade avenges her death by killing the target, but six weeks later, he is still consumed by self-hatred and grief. He visits his friend Blind Al, who tries to convince him to move on, but Wade attempts suicide by blowing himself up. He survives due to his healing abilities and is brought to the X-Mansion by Colossus, who wants to recruit him as an X-Men trainee. Wade agrees reluctantly, believing Vanessa would have wanted him to help others.

While recovering at the X-Mansion, Wade joins Colossus and Negasonic Teenage Warhead on a mission to defuse a standoff involving a young mutant named Russell Collins at a “Mutant Re-education Center.” Wade discovers that Russell has been abused by the orphanage staff and kills one of the staff members in anger. As a result, both Wade and Russell are arrested and sent to the Ice Box, a prison for mutant criminals, fitted with power-suppressing collars. Meanwhile, Cable, a soldier from the future, arrives with the mission to kill Russell, believing he will become a mass murderer.

Cable attacks the Ice Box to get to Russell, and during the chaos, Wade’s collar breaks, allowing him to regain his abilities. Wade tries to protect Russell, but Cable takes Vanessa’s token as leverage. Wade manages to push himself and Cable out of the prison, but Russell overhears Wade’s rejection of him. Near death, Wade has another vision of Vanessa, who encourages him to help Russell. Determined to save the boy, Wade forms a team called X-Force to intercept a prison convoy and rescue Russell. However, the mission goes awry, and all the X-Force members die except for Wade and Domino. Russell frees Juggernaut from the convoy, and they escape together to kill the orphanage headmaster.

Wade, Domino, and Cable team up to stop Russell and Juggernaut. At the orphanage, they struggle against Juggernaut until Colossus arrives to help. Wade attempts to talk Russell down but fails, leading Cable to shoot at Russell. Wade sacrifices himself by jumping in front of the bullet, wearing a power-suppressing collar, and dies, reuniting with Vanessa in the afterlife. This act changes Russell’s mind, preventing him from becoming a killer and saving Cable’s family in the future. Cable uses his last time-travel charge to save Wade by placing Vanessa’s token in front of his heart. With his family safe, Cable decides to stay in the present to help improve the world. Meanwhile, Wade’s friend Dopinder kills the headmaster by running him over.

In a mid-credits sequence, Negasonic Teenage Warhead and her girlfriend Yukio repair Cable’s time-travel device for Wade. He uses it to save Vanessa and X-Force member Peter, as well as to kill an alternate version of himself and Ryan Reynolds before he can make the Green Lantern movie.