The film opens with Wade Wilson/Deadpool (Ryan Reynolds) smoking a cigarette and then pulling out a music box made to look like Wolverine being impaled on a branch like he was in "Logan". Deadpool then rests on several barrels of fuel before he chucks the cigarette into the air and lets it fall into one of the barrels, causing a huge explosion that blows him to pieces. He then proceeds to trash Wolverine for dying in his own movie, saying he can one-up the guy in his own movie.
Deadpool takes us back to a while earlier when he was enjoying his job killing bad guys, up until it brought him to a criminal named Sergei Valishnikov. After outrunning Sergei's goons and getting a ride from Dopinder (Karan Soni), Wade goes home to Vanessa (Morena Baccarin), where they celebrate their anniversary. Wade gives her a skee ball token from their first date, and Vanessa tells Wade that she is ready to have a child and start a family with him, making Wade very excited.
Their happiness is short-lived when a number of goons led by Sergei break into the apartment and attack them. Wade kills the goons, but Sergei shoots Vanessa and kills her. Filled with rage, Wade chases Sergei into the streets. Sergei tries to get away in a car, but he crashes into a van. Wade slams Sergei out of his car and drags him into the street where they are both plowed by a truck, which only kills Sergei.
Wade becomes depressed after Vanessa's death, blaming himself for letting it happen. He goes to see Blind Al (Leslie Uggams), who tries to help him before he does something bad. Wade just does some coke before finally deciding to blow himself up. Wade sees himself in another realm where Vanessa is in their apartment, but he cannot reach her. The bits of his body are recovered by Colossus (Stefan Kapicic), and he takes Wade to the mutant academy.
Wade recovers in the mansion but still screws around, like taking Professor Xavier's chair to roll around in and once again quip that the studio couldn't get better X-Men (but we get a brief glimpse of Xavier, Beast, Cyclops, and Quicksilver in class). He also reunites with Negasonic Teenage Warhead (Brianna Hildebrand) and meets her friendly girlfriend Yukio (Shioli Kutsuna). Colossus tries to encourage Wade to join the X-Men so that he can heal emotionally. Although reluctant, Wade agrees to join them as they are responding to a new mission.
Deadpool, Colossus, and Negasonic go to an orphanage run by the Essex Corporation meant to "fix" mutant children. A 14-year-old boy named Russell Collins, AKA "Firefist" (Julian Dennison) is raging and setting fire to the place. Deadpool tries to talk to Russell and discovers that he is being abused by the Headmaster (Eddie Marsan) and the head orderly after Russell says he would rather go to The Icebox than back to the orphanage. Deadpool shoots the orderly dead, to the horror of Colossus and Negasonic. They try to detain Russell, but he blasts them away with his powers. He and Deadpool are caught and strapped with collars that suppress their mutant powers.
In the future, a mercenary mutant named Cable (Josh Brolin) awakens to the destruction of his home and loss of his wife and child. He takes his daughter's teddy bear as a keepsake before he travels back to the past.
Wade and Russell are taken to the Icebox, where other mutants are kept as prisoners. Russell tries to stick with Wade, despite Wade wanting nothing to do with him. Russell tries to pick a fight with the biggest guy to make him his bitch. They are approached and antagonized by a trio of mutants led by Black Tom Cassidy (Jack Kesy). Wade and Russell them promptly have the crap kicked out of them.
Shortly after, Cable infiltrates the prison to go hunting for Russell. He blasts his and Wade's cell to pieces, but they weren't inside. Cable fights off guards before finding Wade and Russell. Wade fights him, and they fall several feet where Wade appears dead after his body bends unnaturally upon hitting the ground, but the collar fell off him before he did so. Cable asks Wade why he's trying to protect him, and Wade says he's not and that he doesn't care about Russell, which he overhears. Wade takes Cable's gun and blasts them out of the prison. Cable takes the token Wade gave to Vanessa before pounding him so hard in the back that he passes out. Wade goes into the other realm to see Vanessa again, and he still cannot reach her. She looks over to him and tells him his heart isn't in the right place.
Wade goes to his favorite bar to be with Dopinder and Weasel (TJ Miller), where he decides that it is his responsibility to save Russell. With Weasel's help, they decide to form a "super duper fucking group". They set up interviews and meet with a bunch of new mutants - Bedlam (Terry Crews), who can manipulate electrical energy as well as the current in peoples' heads; Zeitgeist (Bill Skarsgard), who can puke acidic bile; Shatterstar (Lewis Tam), an alien who just assumes he's better than everyone at what he does; Vanisher, who may or may not be actually present; Domino (Zazie Beetz), a mutant with extremely good luck; and Peter (Rob Delaney), an ordinary guy who just saw the ad and thought it looked fun. Deadpool hires them all, to the annoyance of Dopinder since he really wanted to get his hands dirty.
Back in the Icebox, Russell finds a potential ally in a mutant with brute strength, hoping to have him on his side.
The team, which Deadpool dubs "X-Force", rides a jet as they attempt to intercept a truck containing mutant prisoners, including Russell. Deadpool warns them to look out for cable. The team leaps out and opens their parachutes, but because of the strong winds that nobody paid attention to, most of the team dies horribly - Bedlam flies headfirst into a truck, Shatterstar gets shredded by helicopter blades, Vanisher is electrocuted on wires (and we discover that he is BRAD PITT), and Zeitgeist lands in a wood chipper. Peter tries to help him out, but Zeitgeist sprays him with acid, causing most of Peter's right side to burn off painfully while Zeitgeist becomes salsa. Deadpool and Domino manage to survive as they catch up to the truck. Domino hijacks the truck while Deadpool fights Cable. During the fight, Cable kills off a bunch of the other mutants, including Black Tom (leading Deadpool to call him racist, even though "Black" Tom was white). Russell then unleashes his mutant buddy...it's JUGGERNAUT (bitch!). He slams his fist through the truck and causes it to tear through a bridge, sending it crashing down. Deadpool starts to geek out because he loves Juggernaut, only for him to actually rip Deadpool in half before he heads off with Russell.
Wade goes back to Blind Al's place where he now has baby legs as they are growing back. Weasel, Dopinder, and Domino all go to him, and Cable shows up as well. He explains to them that in the future, Russell becomes a ruthless killing machine after he commits his first murder with Juggernaut. Russell will eventually become the one who murders Cable's family, so he went back in time to kill Russell before he can begin his reign of terror. Wade convinces Cable to at least allow him to talk to Russell before he has to kill him.
Before heading to find Russell, Deadpool has Dopinder drive him to the X-Mansion to talk to Colossus. He's still upset with Deadpool over his senseless killing, but he tries to appeal to Colossus's good nature by saying how he needs to help Russell.
Deadpool, Cable, Domino, and Dopinder arrive at the orphanage where Russell and Juggernaut are headed to kill the Headmaster. Dopinder takes a look at Juggernaut and decides to go back to the cab. As Deadpool tries to talk to Russell, he ignores him and heads in to go after the Headmaster. The orderlies arrive to attack, so the three mutants proceed to wipe the floor with them. A jet arrives with Colossus, Negasonic, and Yukio arriving to help. They go after Juggernaut, and Colossus finally agrees to fight dirty like Deadpool. They get into a big fight, but Juggernaut proves to be significantly stronger than Colossus. Yukio uses her own rope to bind Juggernaut's legs together before Colossus sticks a loose electrical wire in his ass, and Negasonic uses her power to push Juggernaut into a pool, putting him out for the fight.
Russell reaches the Headmaster as he starts to burn the orphanage up. Deadpool catches up to him and tries to talk Russell down and convince him that killing is not going to make him feel better. Russell refuses to listen and he blasts Deadpool. He gears up to kill the Headmaster, but Deadpool attaches one of the suppressing collars on himself as Cable reaches for his gun. He fires a shot at Russell, but Deadpool leaps in the way to take the bullet, hitting him in the heart. Russell has a change of heart after seeing this sacrifice, and he weeps over Deadpool's body. Cable sees that the blood on his daughter's teddy vanishes, meaning the future is saved. Deadpool accepts his death and says goodbye to everyone (as he waits a very long time to die) as he passes on. He returns to the other realm where he sees Vanessa and he is finally able to reach her. He appears as he did before his mutation, and they talk about how far Wade has come. They kiss passionately, but Vanessa says it's not Wade's time. Cable then uses his remaining charge for his time travel device to go back to when he arrived at the orphanage with Deadpool and Domino. He taps Deadpool's chest before they head in, and after fast-forwarding to the end, Deadpool still takes the shot for Russell, but he finds out that Cable slipped the token in his suit earlier. Deadpool teases Cable because he gave up his last charge to save him, even giving him a hug until Cable puts a knife near Deadpool's dick. Cable decides he's gonna stick around this time period for a while. The whole team starts to walk away until the Headmaster comes out, ungrateful for being spared, and saying that the mutants deserve to die. Cue Dopinder riding in and plowing the guy into mush with the cab as he jumps out gleefully for contributing to the team.
Deadpool continues to walk away with the other mutants, saying that they are his family.
During the credits, Negasonic and Yukio fix Cable's time travel device and give it to Deadpool (and they immediately regret it). Deadpool travels through time to save Vanessa from getting shot and killing Sergei right there in the apartment. He then jumps back to save Peter from dying horribly. He goes back even further to "X-Men Origins: Wolverine" where he kills the proto-Deadpool that fought Wolverine. Deadpool then goes back to when Ryan Reynolds was about to accept the role of Green Lantern, only for Deadpool to shoot him in the head.
*CUT TO THE CHASE*
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Wade Wilson/Deadpool is ready to start a family with his girlfriend Vanessa, until one of his escaped targets breaks into their apartment and kills Vanessa. After Wade kills him in retaliation, he gets depressed and tries to kill himself for failing to save Vanessa, but he is found by Colossus as he once again tries to get Wade to join the X-Men. Deadpool joins Colossus and Negasonic Teenage Warhead to help a mutant boy named Russell Collins (or "Firefist"), who is being abused by the evil Headmaster of the orphanage where he keeps other mutant children and tortures them. Deadpool and Russell end up captured and taken to the Icebox, a prison for mutants.
A time-travelling mercenary named Cable arrives from the future to kill Russell because the boy will grow into a remorseless killer that murders Cable's family. After breaking out of prison, Deadpool forms X-Force to save Russell, only for all the team members except himself and lucky mutant Domino to die gruesomely. Russell befriends Juggernaut and uses him to help him kill the Headmaster. Cable teams up with Deadpool and Domino to prevent Russell from becoming a killer.
The heroes arrive at the orphanage to stop Russell, where they are joined by Colossus, Negasonic, and her girlfriend Yukio to fight. The three X-Men defeat Juggernaut while Deadpool tries to talk Russell down from his murderous rage. It doesn't work, and Russell attempts to go for the kill, leading Cable to fire a shot at him that Deadpool jumps in front of after strapping a collar that removes his mutant ability, meaning he can't regenerate or heal himself. After seeing Deadpool sacrifice himself, Russell has a change of heart, and Cable goes back in time to prevent Deadpool from dying. The Headmaster then tries to insult the mutants until Dopinder arrives to run him over. Deadpool accepts that he has now found himself something of a family.
During the credits, Negasonic and Yukio fix Cable's time travel device, which Deadpool takes for himself and uses to save Vanessa (as well as Peter, an ordinary guy on X-Force), kill the phony Deadpool from "X-Men Origins", and also kill Ryan Reynolds before he can agree to make Green Lantern.
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