Foul-mouthed mutant mercenary Wade Wilson (a.k.a. Deadpool) assembles a team of fellow mutant rogues to protect a young boy with supernatural abilities from the brutal, time-traveling cyborg Cable. After failing to kill one of his targets, Wade's girlfriend Vanessa is murdered. Blaming himself, Wade attempts suicide but is saved by Colossus. Recovering at the X-Mansion, Wade joins the X-Men and teams up with young mutant Russell Collins to escape prison and defeat Cable. Along with a team called X-Force, Wade and Russell confront the abusive headmaster of Russell's orphanage and alter their futures, with Wade sacrificing himself to save Russell. However, Cable uses his time-traveling device to undo Wade's death and change the future, leading to a mid-credit sequence where Wade uses the device to alter various events.

After being experimented on and left disfigured but with superpowers, Deadpool embarks on a mission to track down the man responsible. Along the way, he fights off numerous thugs, clashes with the X-Men, and confronts his own fears and insecurities. Ultimately, Deadpool manages to rescue his love interest, Vanessa, and exact his revenge on the villain Ajax, all while providing plenty of wisecracking and fourth-wall-breaking humor.

A listless Wade Wilson toils away in civilian life with his days as the morally flexible mercenary, Deadpool, behind him. But when his homeworld faces an existential threat, Wade must reluctantly suit-up again with an even more reluctant Wolverine.