This film is nonlinear, jumping between present and past. The plot is in chronological order.
Wade Wilson, a former special forces operative working as a criminal enforcer, meets a prostitute, Vanessa, at a bar. The two develop a relationship, and a year later Wilson proposes marriage. He is then diagnosed with liver, lung, prostate, and brain cancer. Despite Vanessa’s love, Wilson dislikes the thought of her watching him waste away, and he leaves her in the middle of the night.
A recruiter from a covert organization approaches Wilson and promises him abilities that will cure his cancer. Wilson reluctantly agrees. He is taken to a remote laboratory where he meets Ajax and Angel Dust, and instantly hates them. Ajax injects a mutation-activating serum into Wilson and subjects him to daily torture to activate it but Wilson’s body fails to respond. Wilson then finds out Ajax’s real name is Francis and mocks him. Annoyed by that Ajax asphyxiates him in an oxygen chamber, causing him to develop an accelerated healing factor that cures him but leaves him disfigured with burn like scars over his entire body. Ajax reveals to Wilson that he does not actually intend to make him a superhero, but instead will sell him to someone else as a “super slave”. Wilson finds a way to escape his confines and destroy the lab. He fights Ajax, but relents when Ajax says that he can repair his appearance. Ajax then impales him with rebar and leaves him for dead in the burning building.
Wilson survives and attempts to return to Vanessa, but is afraid of her reaction to his disfigurement after people on the streets appear to be scared by his appearance. After consulting his best friend Weasel, Wilson begins the task of tracking down Ajax to get the cure. He becomes a masked vigilante, adopts the alter ego “Deadpool”, and resides with an elderly blind woman, Al. Following a string of leads, Deadpool tracks Ajax to a convoy on an expressway. He executes the numerous convoy guards, subdues Ajax, and demands the cure to his disfigurement. He is interrupted by Colossus and Negasonic Teenage Warhead. They try to convince him to join the X-Men, and Ajax escapes. They handcuff Deadpool, who had gotten himself incapacitated trying to fight Colossus, but he frees himself by severing his own hand, which later regenerates.
Ajax and Angel Dust go to Weasel’s bar and learn about Vanessa. Weasel warns Wilson that she is in danger, and they go to the club where she works to warn her, but Wilson hesitates. Ajax and Angel Dust abduct Vanessa and tell Wilson to meet them at a decommissioned helicarrier in a scrapyard. Deadpool persuades Colossus and Negasonic to help him rescue Vanessa. They travel to the scrapyard and battle Ajax, Angel Dust, and their team of mercenaries. As Colossus and Negasonic fight Angel Dust, Deadpool kills most of the mercenaries and engages Ajax in hand-to-hand combat atop the helicarrier. Negasonic accidentally destroys the equipment stabilizing the helicarrier during the fight, tipping it and scattering Ajax and Deadpool. As Colossus carries Negasonic and Angel to safety, Deadpool saves Vanessa and incapacitates Ajax. When Deadpool demands that Ajax “repair” him, Ajax laughs and reveals that there is no cure. Deadpool kills Ajax in response, despite Colossus pleading him not to. Vanessa is initially furious with Wade for abandoning her, but they reconcile after she learns why he did not return.
In a post-credits scene, Deadpool tells the audience that the film is over and announces a sequel featuring Cable.