The Mushroom Kingdom has become a Vice City following the massacre of Kirby the Cannibal eight years ago, imprisoned by the Super Mario Bros.. A Mob War has since begun between mob bosses Bowser, Ganondorf, King Dedede, and Mewtwo, with Princess Peach trying to keep rule over her kingdom. She frequently sleeps with both the alcoholic Mario, and drug dealing Luigi. A new serial killer named the Butcher begins disembowelling civilians, including Pichu, Roy, and then Mewtwo, breaking the stalemart between the dons. Peach goes to interrogate Kirby, but is kidnapped by the Butcher.
Luigi sets out to find Peach, assuming Bowser was responsible. Aided by Samus Aran, and Mewtwo’s associate Red, Luigi goes to Tingle’s gay bar, but Captain Falcon and Pit deny knowing Bowser’s location. Luigi is abducted by Donkey Kong, meeting Ganon. He offers information if Luigi delivers the Triforce to Captain Olimar, a deranged preacher in the slums. On the way, Luigi is caught in a fight between police officers Marth and Ike, and a gang led by Fox McCloud. Ike is mortally wounded, dying in hospital. Luigi meets Olimar, who claims the kingdom will be devoured by demons, crafting a bomb, which Luigi returns to Ganon.
Police Chief Link declares Princess Zelda as regent until Peace is found, declaring martial law. Ganon informs Luigi that Bowser and King Dedede are meeting at the latter’s brothel. Luigi speaks with Dedede, who agrees to bring about peace with the Super Mario Bros. Mario arrives at the brothel, beating Donkey Kong to death upon learning he is dating his ex-girlfriend Pauline. During the brawl, Luigi discovers Dedede has been murdered by the Butcher. A police raid led by Link’s agent Sheik occurs, prompting Luigi, Mario, Samus, and Pit to go underground. Alongside Red, the group confront the greedy informant Wario, who claims news anchorman Lakitu knows Bowser’s location. However, after interrogating Lakitu, Wario betrays the brothers to the police. Mario fends them off with Yoshi, but the others are arrested.
In custody, Luigi learns from Link that he arranged the meeting with Dedede, the raid unauthorised. Luigi interrogates Kirby, who ate his girlfriend Princess Daisy. Mario and Captain Falcon launch a jailbreak. Kirby escapes confinement, but is confronted by his guard Meta Knight. Luigi escapes with Falcon, Samus, Pit, and Red. Wario ceases the rioting, claiming Meta Knight incinerated Kirby, but has disappeared. Link, Zelda, and Wario retreat to the Nintendo and Hal Labs skyscrapers to evade Mario’s intended civil war. Mario discovers Olimar is building a Doomsday Cult to bring about the Apocalypse, but Mario convinces the downtrodden citizens to instead take back their home. Returning home, Mario discovers Yoshi has been murdered by the Ice Climbers, Wario’s minions.
Luigi’s group encounter Ganon, who teleports Luigi to Bowser’s lair. Beforehand, Captain Falcon and Pit decide to flee the city. Bowser, now a Buddhist, reveals Ganon kidnapped Peach and controls the Butcher, hiding in the skyscrapers. Olimar’s demons turn out to be the collective Mr. Game & Watch, the oldest citizens in the kingdom. Bowser commits suicide when the Game & Watch attack. Red is killed using the bomb made for Ganon, given to him by Wario’s handicapped brother Waluigi.
Mario leads an army of civilians against Bowser’s forces. Game & Watch transforms into a gigantic octopus, skewering multiple characters including Olimar and Fox, but Mario destroys it. When Wario admits he murdered Red, he is killed by Red’s girlfriend Leaf, using a Jigglypuff. Zelda betrays Link, in a secret romance with Ganon. However, a healed Link returns, asking Zelda to help rebuild the fallen Hyrule together, but Ganon murders them. Luigi discovers the Butcher keeps trophies of his victim’s bodies, including the dead Peach. The Butcher is revealed to be two boys, Ness and Lucas, who developed psychic powers under Mewtwo’s tutelage. Samus, Captain Falcon, and Pit arrive to fight the Butchers.
On the roof, Luigi discovers Kirby is alive, the true master of the Butchers, having driven Mewtwo into madness to create super soldiers. Kirby decapitates Ganon, and attempts to murder Luigi, but Luigi destroys the rooftop with a fireball. Luigi recovers in hospital, the surviving community coming together under the leadership of Marth as the new Police Chief.
Luigi receives a telephone call from Kirby, who congratulates him on conquering his demons, before hanging up with the implication he intends on eating Shigeru Miyamoto and Masahiro Sakurai.
