After the Mushroom Kingdom's citizens begin to fall victim to the "Blorbs," a mysterious disease that affects Toads and makes their bodies swell to enormous proportions, Princess Peach summons a conference to find a solution for the problem. The conference is attended by Mario, Luigi, Dr. Toadley's intern, some Toads, and Starlow, a star sprite. As Peach is explaining the effects to the attendees, Bowser barges into the room, trying to be a part of the meeting too. However, since his interruption is interpreted as an attempted assault, he is attacked and quickly defeated by Mario. Peach and Starlow then use their powers to send him away to Dimble Wood. After recovering from his defeat, Bowser receives an item called a "Lucky Mushroom" from a mysterious merchant in a gray cloak. Unbeknown to Bowser, the cloaked person is actually Fawful, who tricked Bowser and also was the cause of the blorb epidemic (by selling "Blorb Mushrooms" to the toads). His present quickly turns out to be a "Vacuum Mushroom", an Item which causes strange effects to take place in Bowser's body and enhances his breath. The enhancement gives Bowser the ability to inhale everything, but also allows Fawful to control his actions. Using this newly gained influence, Fawful then sends Bowser back to Peach's meeting, where he uses the Vacuum Shroom's powers to inhale everyone. While Bowser gloats about his victory, he mysteriously falls unconscious, and Fawful sends his minion to take him away.
After being inhaled, Mario reawakens inside Bowser's Body, being reduced to microscopic size. While traveling through the Trash Pit and encountering a few hostile immune cells, he eventually stumbles into Starlow, and then Luigi. After being reunited, the trio sets out to find Princess Peach. As they try to escape the place, they find a Nubbin, an object resembling an exposed nerve. They activate it by hammering it, which rouses Bowser and breaks his unconsciousness. He awakes inside Cavi Cape. He begins to head out of this strange place and soon discovers that he has lost the ability to breathe fire. Angry about the loss of his flame, he starts to head out of the cave. After leaving the caves he meets Fawful, who proclaims that he is planning to claim Bowser's Castle as his own and to conquer the whole Mushroom Kingdom. Fawful then flees, and before Bowser can give chase, he is halted by Midbus, a minion of Fawful. Bowser battles him, but because his body was weakened by the Vacuum Mushroom, he is quickly defeated. When Midbus leaves, Bowser then sets out north, towards his castle. Before he can get there, he has to cross Plank Beach which lies between Cavi Cape and his home. Soon after he begins his journey homeward, he is confronted by a mysterious voice explaining the concept of Chakroads to him, portals allowing him to quickly traverse the Mushroom Kingdom. At Plack Beach, Bowser meets Broque Monsieur, a famous block collector, trapped on a small island. Initially reluctant, Bowser agrees to help him when Broque Monsieur offers him the Vacuum Block, an object that gives its user the capacity to use a powerful suction attack. Bowser pulls on the rope connected to the island, but does not have the strength to pull the island over. The bros then help out by boosting his arm muscle. After successfully completing this task, he yanks the island onto the beach. Now rescued, Broque Monsieur gives Bowser the Vacuum Block and teaches Bowser the vacuum ability. With that new power, Bowser continues north. At the northern side of the beach, Bowser comes across the Sea Pipe Statue, a fountain dedicated to a hero of the sea. Because it doesn’t look like Bowser, he begins to destroy it. Unbeknown to Bowser, Fawful has imbued it with the power of self defense, and it attacks him. After Bowser deactivates it, the statue turns back into a water fountain. Drinking from it, Bowser inadvertently opens a path allowing the Mario Brothers to advance further into him. They enter the Pump Works and venture through it. Deep inside, they find the Stingler, a key-like item that opens the path to the Flame Pipe where Scutlet blocks Bowser's flame. After the bros. defeat Scutlet, Bowser is able to breathe fire again. He uses this rediscovered skill to continue northward, and defeat Broggy, Broque Monsieur’s pet dog. Bowser then heads into Dimble Wood. In the forest, Bowser runs into Broque Monsieur again, this time inside his shop. As Bowser is leaving, Broque Monsieur asks him to do a favor while he's on his mission: to recover some Blitties for him. Bowser also finds some trapped Goombas, who were caged by Fawful. After freeing his minions, Bowser is able to use his minions' special move, Goomba Storm. Near the end of Dimble Wood, Bowser meets up with three of his troops: Sergeant Guy, Corporal Paraplonk, and Private Goomp, whom are attempting to retake the castle using a Banzai Bill cannon, but they realize they are out of ammunition. Bowser then heads to a farm maintained by a family of Wigglers. He finds a giant carrot, thinking it would be a nice alternative to a Banzai Bill, and plunks it out, making the Wiggler guarding it furious. Bowser asks if Wiggler has a Banzai Bill, which luckily, he does. He tells Bowser to eat the carrot in sixty seconds if he wants the Banzai Bill. After completing the task (with the aid of the bros. in the Gut Check), Bowser reminds Wiggler about the Banzai Bill, but Wiggler seems to forget the previous conversations. Wiggler is furious with Bowser for eating the carrot, and attacks him. After being defeated, Wiggler gives Bowser the ammunition, telling him to leave immediately. Bowser starts to head back to his minions, but is stricken with horrible pain. The Mario Bros. find the source, a giant worm-like creature named Durmite, who is causing rampant inside Bowser. A battle emerges, and after defeating Durmite, it shrinks down to the size of Mario’s foot and takes off. They explore the area and find Toadbert. After the bros. hit a switch in that area, Bowser learns the Sliding Punch.
Bowser returns to the cannon and fires the Banzai Bill at his own castle. Midbus, however, lifts the castle over the missile, and lands the castle in Dimble Wood, on top of the unprepared Bowser. Heading to the Rump Command, the Mario Bros. reawaken him with adrenaline, unintentionally growing Bowser to the size of his castle. He engages it to battle, which significantly damages it enough for Midbus to retreat. Bowser shrinks to normal size and travels north through the newly created path. Bowser chases after the castle, having trouble with Midbus, who keeps the castle in air. When Midbus fires a giant iron ball at Bowser, Mario and Luigi boost his arm muscles, allowing Bowser to launch it back to Midbus, knocking the castle back to the ground. At the castle, he discovers that his minions have been brainwashed by Fawful. He also finds that his military training facility has been turned into Fawful Theater. When he enters the theater, he finds no seats to sit on, but a brainwashed Goomba takes him to a VIP seat. Fawful then appears and announces that Bowser is his special guest, and Bowser is launched onto the stage. Fawful brings out Midbus, and Bowser is forced to battle him in a caged fight. After Bowser defeats Midbus, he is taken by some Boos to a winner’s feast. Here, the Boos trick Bowser into eating so much food that he becomes obese and is stuck in the floor from his extra weight.
While exploring the newly opened area, the Mario Bros. find Princess Peach. However, she is kidnapped immediately by Kretins. They chase the creature through the Flab Zone, until it is cornered at a dead end. After battling Alpha and Beta Kretin, they learn the plot of Fawful’s plan, which involves the Dark Star, an evil ancient artifact under Toad Town, and Peach herself. As they try to find a way out, Fawful uses a laser-like machine to pull Peach from Bowser, kidnapping her. Midbus then brings a treadmill, which Bowser falls onto, and literally burns the extra calories. Bowser then sees a sign saying "no open fire", while accidently bumping into a Bob-omb. The lit Bob-omb hops into a huge pile of Bob-ombs, and explodes, launching Bowser to the Underground Tunnel.While making his way through the tunnels, he meets a few of his Monty Mole minions, who are creating a secret escape route for Bowser connecting to Toad Town Tunnels. With Bowser’s help, they finish the path to the underground Toad Town. Bowser heads through a path that activates a security system, knocking him unconscious. This causes a pipe blocking a path in the Pipe Yard to break and fall, allowing the trio to exit Bowser’s body. They find themselves in Toad Town Tunnels too, and head to stop Fawful from gaining the Dark Star. When they arrive, though, they are too late. Fawful takes the Dark Star and heads for Peach’s Castle. Just as the bros. are about to enter the castle, barriers are formed by the Dark Star’s power, leaving no entrance available. They then head for Doctor Toadley, searching for an answer to the cure for the blorbs, another unsolved problem. Just as they enter his office, Bowser enters and engages the bros. in a battle.
After Mario and Luigi defeat Bowser, the doctor explains to the three of them that they need to collect the three Star Cures to cure the blorbs and possibly find a way into the castle. He then tells them that the first Star Cure is held by Durmite, located in Dimble Wood. Bowser overhears this, and dashes toward Dimble Wood to get a head start. But the three of them know that Durmite is now in Bowser’s body, and head back to find the first sage. As soon as they re-enter Bowser, they spot Durmite, whom they begin to chase. However, they are soon stopped by a mysterious wall of Boo Blocks, which Durmite ran past. Bowser, on the other hand, is at Blubble Lake. He runs into a propeller machine that he activates by sneezing (the sneeze, too, was powered up thanks to the Mario Bros.). The tower comes out of the water, and lands on Bowser. To cure him, the trio heads back to the Rump Command, increasing Bowser’s size again. Bowser then attacks the Tower of Yikk and defeats the moving tower. Bowser returns to normal and enters the quiet tower. He enters a room, where he finds the ghost of Yikk, who is owner of the tower.Yikk explains his invention, the Boo-Ray Machine, that enables various effects on Boo-related things. From the ray, the Mario Bros. are able to go through the Energy Hold inside Bowser and catch up to Durmite. Then they battle her, in her sage form known as Wisdurm. After she is conquered, Wisdurm turns into a butterfly and willingly gives the first Star Cure to them. They find the exit, and enter a new area where they activate the Body Slam, allowing Bowser to leave the Tower. Bowser immediately finds Private Goomp, then asks him if he has seen a Star Cure. Private Goomp tells Bowser about a Star Cure-like object in Bowser’s vault at his castle. Making his way back to his castle, he uses his new move to explore the remains of his castle. When making it to his vault, he finds that the railroad he had helped with near Toad Town has been installed through the vault. Worse, the railroad is now property of Fawful, and is used by the Fawful Express. The earlier Monty Moles are now under control of Fawful. Enraged by the treason, Bowser spits fire at the Monty Bros., but they dodge it. The Fawful Express prepares to leave Bowser’s Castle, whilst Bowser is on the tracks, looking for the safe with the Star Cure. As Bowser tries to stop the train from crushing him, he trips, and is crushed into a rock. The Mario Bros. quickly grow Bowser in size, much larger than the train. Bowser takes revenge, and destroys the train. Returning to his vault, Bowser finds the safe the Star Cure is in, but he has forgotten the code. The Mario Bros. journey to Bowser’s Memory Banks, where they search for the missing information. After arriving in the main part of the area, a strange creature scans the bros., and creates blocky duplicates of the bros., to battle them. Once they defeat their counterparts, the creature reveals that it’s the guardian of Bowser’s Memory. It shows the bros. that the safe’s combination has been damaged in his memory, and that the bros. need to repair it. After they solve the puzzle, Bowser abruptly remembers it, and sings it in a short poem. He finally opens the safe, and grabs the second Star Cure. Private Goomp, Sergeant Guy, and Corporal Paraplonk quickly shove Bowser in the safe, saying that Fawful promised them extra rations for their work. Angry at his former minions for betraying him, he swallows the Star Cure. The Marios find it in the Gut Check and head back through the pipe to Toad Town.
Doctor Toadley tells the Marios that the final Star Cure is somewhere above Plack Beach. His intern gives them Birdley to guide them to the last Star Cure. Journeying there, they discover a mountainous path that they never visited before. At the top of the path, they meet the last sage, Chakron, who is also the owner and inventor of the Chakroads. He explains that he would give the Mario Bros. the last Star Cure, but is stuck in his 1000-year pose, and needs help breaking free. After failing to move him an inch, he hints that a special attack in Dimble Wood would help. The trio then heads for Dimble Wood, where they search for the Attack Pieces for Snack Basket. After finding six of them and gaining access to a new area, Mario is kidnapped by a Sockop. Luigi chases it, but ends up trapped in a knocked-out Sockop. In a scene reminiscent of Super Mario Bros. 3, Luigi uses this new ability to hop across thorns, and rescue Mario. In the process, Luigi is able to collect the remaining attack parts and complete Snack Basket. Heading back to Chakron, the three of them use the new move, and succeed. For releasing Chakron from his pose, and giving him a new pose he intends to hold for 1000 years, he gives the bros. the final Star Cure.
Mario and Luigi return to Doctor Toadley at the clinic. Taking all three Star Cures, the doctor creates the Miracle Cure, which he uses to cure the blorbs. After completing the process, all the infected Toads are now back to normal. Then the Miracle Cure returns to the Marios, and they take it to the gates blocking Peach’s Castle. Using the Miracle Cure, they are able to break the barriers and head into the castle. After searching for an entrance to the castle, they run into a giant pile of trash. As Starlow ponders over why it’s there, Midbus comes in and activates a remote. This causes the garbage to come to life and form the robotic Junker. However, Junker starts malfunctioning and it doesn't obey Midbus's commands properly. Only after Midbus smashes the remote in anger does Junker finally attack the bros. After receiving enough damage, Junker malfunctions again, rampaging around wildly, freeing Bowser and opening a path in the process. However, Bowser has been in the safe for so long that the small space has given him a horrible back pain. Heading through the secret path to a nearby pipe, the Marios find themselves once again inside the Koopa King. After searching quite a bit, they find Toadsworth inside the Lumbar Nook. He explains that to heal his back, the Mario Bros. must drill into the center of the back. After a very long time (so long that Toadsworth and Toadbert drink some tea to relax), the shock causes Bowser to loosen up his back, enabling him to use the Spike Ball move. After that, Bowser sets off in search of Fawful and the Dark Star. During his search, Bowser is confronted by giant Piranha Plants that burn him and force him into curling up into a spike ball. The bros. then go to the Chest Station to give impulses that make Bowser fly up so he can fight the Piranha Plants. Not long after defeating them, Bowser finds Fawful and Midbus waiting for the Dark Star to awaken. To aid Midbus, Fawful grants him an ice-based power up, transforming into Blizzard Midbus to attack. After defeat, Midbus's entire body freezes, with icy air blowing from his nose. Meanwhile, Fawful is absorbing Dark Star’s power, with Bowser punching him before it is complete. Laughing at how that was fun, the awoken Dark Star enters Bowser's body, into the Airway. The heat is so strong that Bowser has to breathe in the cold air emanating from the frozen Midbus. With the help of the cold air, Mario and Luigi chase the Dark Star, with it escaping several times and absorbing some of Bowser’s DNA. When they finally trap it into a dead end, Dark Star finally attacks the Marios in battle. Even after defeat, the Dark Star has enough DNA to allow recreating most of Bowser’s body and power for himself. It escapes from Bowser and runs off, with Bowser chasing after him.
Bowser finds Fawful in the conference room after he defeats the Super Peach's Castle, which Fawful had actvated. The dark power Fawful absorbed allows him to transform into Dark Fawful. Bowser then fights Dark Fawful, and destroys his body. Somehow, though, he survives as a dark ball of energy. Dark Fawful escapes, but is absorbed by Dark Star. With the two parts back together, Dark Star completes the transformation into Dark Bowser, and escapes through a hidden passage. Bowser fights Dark Bowser in a final minigame when the two engage in a quick Spike Ball battle (again provided by the bros.' work at the Chest Station), with Dark Bowser escaping to a tower of the castle. Bowser finds Dark Bowser on the tower high above the Castle. The princess is next to Dark Bowser, unconscious. Dark Bowser states that he will conquer the Mushroom Kingdom, creating an age of darkness. He then traps the citizens of the kingdom within a giant dark hurricane, with Bowser struggling to withstand the force. Starlow then reveals the truth to Bowser: Mario and Luigi are within his body, and she asks him not to forget that they are in there to help. However, Bowser can barely hear with all the wind in the area. Bowser then states that Dark Bowser will never take over his kingdom, and duels Dark Bowser to an epic final battle. They both breathe fire and the battle rages on, with Bowser easily defeating Dark Bowser. But, Dark Fawful revives him and turns him giant. Bowser then punches his belly, causing Dark Fawful to be ejected from his body, enabling Bowser to vacuum him up. With Dark Fawful and Dark Star Core inside, the Marios are able to attack all of them. After a long battle, the Dark Star Core and Dark Fawful are defeated, leaving Dark Bowser unstable. Mocking him, Bowser punches Dark Bowser until he can’t take any more and explodes. The explosion frees the Mushroom Kingdom from the Dark Star’s influence forever. Inside Bowser’s body, Dark Fawful is still alive and speaks to the Marios. As he fakes remorse over what he has done, he tries one final attempt to destroy the Mario Bros., and explodes. This explosion actually causes all of the people inside of Bowser to be sent back to the Mushroom Kingdom. The now-conscious Peach, along with other Toads, moves to congratulate the Marios on a job well done. Bowser, confused and angered, realizes that the Mario Bros. were inside his body. When Starlow tries to calm him by telling Bowser to forget the past, Bowser recognizes Starlow’s voice as "Chippy". When she confirms this, Bowser goes crazy. The Toads and the Princess flee from the scene, and as Bowser promises another epic battle with the Mario Bros., the credits roll. Mario and Luigi then defeat Bowser and he is carried back to his castle by his minions.
Afterward, Bowser is seen lying in a bed at his castle, nursing injuries given to him by the Marios. Private Goomp, Sergeant Guy, and Corporal Paraplonk are there, begging and apologizing for their treason and wanting to rejoin his army. Just then, Birdley comes flying in and drops a present on Bowser’s bed, with Starlow popping out. She came to check on him, afraid that he might attack Peach's Castle again. However, Bowser says he merely wants to fix his castle before doing any more evil. Afterward, still angry at the truth, Bowser yells at Starlow to leave, which she does. Bowser yells at the three traitors, telling them to go fix his castle. They are speechless, since that meant that they are back in the Koopa Troop. They run off, yelling only thanks, leaving Bowser to himself. Looking around to see if anyone was there, Bowser opens the present, and finds a cake with himself, Mario, Luigi, and Peach on it. If the player plays the game after it is beaten and the ending is done, the game will just start from the last save point, before the final battle. Template:Br