Following the events of Waluigi Unleashed, Waluigi retired from public view and lives as a rugged lumberjack in the backwoods of the radioactive Forest Kingdom. One night his place of residen is assaulted by a squad of mushroom kingdom spec-ops. Toad emerges from the shadows and explains that Waluigi's services are once again required: Primate Alliance cultists are attempting to create a bio-mechanical god.
Waluigi refuses, bu Toad explains that during his operation at the hand of the resistance, his body was stuffed with explosive nanobots which can be detonatd with a remote killswitch. Waluigi reluctantly accepts but insist he needs to form a "killer crew". For the purpose of the mission, Waluigi selects the notorious mercenary Oogtar, Lakitu (known for his "skills in genocide") and a cyborg Goomba named Goomborg. Before investigating the cult proper, the team is tasked to board the international space station, taken over by Tiny Kong who uses it for ion strikes against civilian population centers.
The team heads to Koopa City to board the last surviving space shuttle launch pad. Once there, they find that the shuttle is guarded by Funky Kong, a sight that greatly distrubs Waluigi as he alredy killed him once. After Funky Kong once again ends his life with the cryptic words "There are things you will never understand", the soldiers board the space station. Fighting their way through it, they find Tiny Kong in the control room. Tiny Kong explains that the Primate Alliance goal's is to destroy all infrastructure modern society relies on to impose the Primate Alliance's strict millitary rule. The cultist are not part of the primate alliance, but rather an unrelated group supplied by it to hasten the collapse of the Mushroom Kingdom. The ape uses the opportunity to kill Goomborg and espaces with an espace pod the space station's as the self-destruct sequence is initiated.
Escaping the space station, Waluigi lands the space shuttle on the cult's purpose site of activity. As they reach the heart of the complex, Lakitu announces that he was a plant for the cultists and kill Oogtar. Waluigi is captured and taken before the cult's leader: Ashley. Having survived the Great Ape War, Ashley rejected witchcraft and embraced cybernetics. She expalins that the cultists are using ancient technology to create a boi-mechanical kaiju in the effige of Bowser, which will use its mind-control rays to bring the entire populace under their control.
Again empowered by a vision, Waluigi breaks free from his restraint and fights Ashley. Victorious, Waluigi throws her into the fusion core of the facility, destroying it. Waluigi receives a messagge from Toad tersely congratulating him on his victory and promising a new mission, but Waluigi departs the rubbles, looking for answer...