Wesker is first shown speaking to Dr. Doom in the prologue comic. He overhears a plan to steal the power of Galactus, the Devourer of Worlds. Wesker is intrigued, believing the name "exudes power". After Galactus becomes a threat to both worlds he seemingly joins the heroes and villains of both sides to stop him. Of course, if Wesker is not used by the player he may turn out to be one of Galactus' Heralds. However, it is revealed in Wesker's arcade ending that he was simply standing by as the others fought him so that he could overtake them when they're all weakened. Wesker is later shown in an unidentified research lab, having captured all of the heroes. He wonders aloud to himself which one of them has the potential to "become the next Alexia or Lisa Trevor".
Alternatively, Wesker is shown in Chris' ending being prosecuted by none other than Matt Murdock (a.k.a. Daredevil, the Man Without Fear). Wesker is restrained in a straight jacket and is directly accused of the Raccoon City Incident of 1998. Wesker openly gloats that he "caused quite a mess there." He attempts to undo his restraints and resist the bailiff, but is stopped by Chris, who threatens to pin him to the floor. Wesker is briefly mentioned in Hulk's ending, and after the Hulk easily disposes of the Nemesis, Chris advises to "take it easy" on Wesker. In Dormammu's ending, Wesker appears with other villains, plotting when to take over both worlds.