In Deadpool the player takes control of the loud-mouthed, foul-mouthed, merc-with-a-mouth Wade Wilson (a.k.a. Deadpool). While on out on a contract to kill a corrupt media mogul, Mister Sinister intervenes and kills him instead, drawing the ire of Deadpool who then vows revenge only to stumble upon a bigger plot which could spell the end of humanity.

With the help of some of the X-Men such as Wolverine, Rogue and Domino along with a buddy from the future, Cable, they band together to stop Mister Sinister and his group of Marauders (Arclight, Blockbuster and Vertigo) from succeeding.