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The plot continues from Diaper Duty 3: Baby Peach's Turn to Shine
When Baby Bowser orders Kamek to experiment with his magical creations he accidentally combines a regular Piranha Plant with a Fire Flower and a Super Mushroom creating a Super Piranha Plant, the monster is out of Baby Bowser and Kamek's control and goes on a destructive rampage and breaks out of Kamek's lab. The Piranha Plant, named Super Piranha by Kamek goes on a destructive rampage through Toad Town the new home town of the Baby Mario Brothers, they instinctively jump into action against the giant monster however they are swallowed whole by the great beast and he continues on to eat the other star children. Baby Bowser thinking only of himself like always flees with Kamek back to his castle to figure out his next scheme. Seeing the threat from above in the castle Toadsworth sends Baby Peach out to space with Baby Rosalina, hoping that the girls will be safe, he then finds E. Gadd who has been appointed the Royal family's inventor and the two set off to destroy the beast however they too are conquered by the gigantic beast.
Super Piranha is mad after the attack and finds a large city, Diamond City. Baby Wario and Baby Waluigi see the plant coming and go to warn the others babies at the park but he eats Baby Wario and Baby Waluigi who already have a reputation of bullies and are picking on other babies in the park. Super Piranha swallows them whole, Diamond City sends out an open message to everybody to escape into space it's the only safe place. Many of then do but many are also eaten by the monstrous plant. Toadsworth get the message and sends it to Donkey Kong Island and tells them to past the messages on. Over on Donkey Kong Island Cranky Kong who has been experimenting with potions and inventions puts his children Baby Donkey Kong and Baby Swanky Kong in a barrel blast aiming up at the space station run by the Lumas, they are hurled up into space followed by their friend Funky Kong. Baby Candy Kong remains on the island with Wrinkly Kong and Cranky Kong.
The King and Queen of Sarasaland receive the message as well and they send their young daughter up into the sky to keep her safe from harm, just in the nick of time too because Super Piranha eats the castle just as Baby Daisy is propelled upwards. Yoshi however does not receive the message and he is swallowed by Super Piranha, he sets up his base on Yoshi Island much to the dismay of the other Yoshis and Birdos on the island who have been forced into slavery planting more Piranha Seeds making more and more Piranha Plants. Up on the space station Rosalina, Peach, Donkey Kong, Swanky Kong, Funky Kong and Daisy discuss what to do next, the babies are scared but they know that they must head back down to the Mushroom World and save their friends! Rosalina tells Daisy, Swanky Kong and Funky Kong to stay behind to take care of the Lumas with a lot of protest. Rosalina, Peach and Donkey Kong jump into a Shroom Ship and head back down to Toad Town which has been ravaged by destruction and is even know plagued by Piranha Plants under the rule of none other than Petey Piranha. The babies free the town from the Piranha Plants and beat Petey banishing him to the tropical islands. They continue on through the castle to see that it's completely destroyed and there is nothing left behind only one side of the castle which has received severe damage. They see that here Kammy Koopa has become a squatter and is attacking the babies as they try to free the castle, they see a lone Toad in the castle they then propel the Toad up to space for protection.
Up in space the three babies have become very bored, Baby Funky has found something to do trying to construct a plane for the three of them, while Swanky has found a microphone which he is annoying everybody with and Daisy has found a soccer ball which she has been kicking around for fun. Toad finds them and cries only to be consoled by the babies who have dubbed themselves The Space Babies. Donkey Kong, Peach and Rosalina find themselves in the desert nation of Sarasaland which is also destroyed by Super Piranha, Tatanga has nestled himself here and has let his minions out, he is also defeated by the three babies and they progress to save the rest of the Mushroom World.
The three star babies down on the Mushroom Plant find that Prince K. Rool is again trying to take over Donkey Kong Island now that it has been ravaged by destruction. Cranky Kong and Wrinkly Kong are fighting against the Prince together, Cranky Kong has made several potions he has given one himself he dubbed Strong Kong and one to his wife he calls Mini Monkey. The babies come to provide the two back up and they defeat the young Prince. Their final stop is on Yoshi Island and they find Super Piranha here however before they go anywhere on the island a plane flies down from the sky and Toad, Funky Kong, Swanky and Daisy join in with Toad and his spore attacks, Funky and his Pineapple Launcher, Swanky and his Sonic waves and Daisy and her projectiles with balls join up with the Star children. They defeat Super Piranha and he exhaled goop and Baby Mario, Baby Luigi, Baby Wario, Baby Waluigi and Baby Yoshi fall out, all crying. After the babies calm down the free the Birdos and the Yoshis that were forced into slavery on the island
- Baby Peach - One of the three star children that are playable in the game, she is playable in all five chapters and in most levels in these chapters. She uses frypans and umbrellas to attack.
- Baby Donkey Kong - One of the three star children that are playable in the game. He is playable in all five chapters and in most levels. He uses his "Simian Strength" to attack.
- Baby Rosalina - One of the three star children that are playable in the game. She is playable in all five chapters and in most levels. She uses star powers to attack.
- Baby Daisy - One of the self dubbed "space children" that are left up on the Luma space station she is playable only in the final chapter of the game. She uses various balls as projectile attacks.
- Baby Funky Kong - One of the self dubbed "space children" that are left up on the Luma space station he is playable only in the final chapter of the game. He uses a gun he created called the pineapple launcher, he says that it's just a prototype.
- Baby Swanky Kong - One of the self dubbed "space children" that are left up on the Luma space station he is playable only in the final chapter of the game. He uses his sonic waves from his microphone to attack. He states that he hates fighting but he loves the mic.
- Toad - One of the self dubbed "space children" that are left up on the Luma space station he is playable only in the final chapter of the game. He uses spores from his head to attack, he states that he should have brought his bazooka into space with him.
- Baby Mario - Eaten by Super Piranha in chapter one
- Baby Luigi - Eaten by Super Piranha in chapter one
- Baby Wario - Eaten by Super Piranha in chapter two
- Baby Waluigi - Eaten by Super Piranha in chapter two
- Baby Yoshi - Eaten by Super Piranha in chapter three
- Toadsworth - Eaten by Super Piranha in chapter one
- E. Gadd - Eaten by Super Piranha in chapter one
- Baby Bowser - Runs away in chapter one
- Kamek - Runs away in chapter one
- Super Piranha - The super Piranha experiment of Kamek he is the result of a fire flower, super mushroom and Piranha plant fused together by dark magic. He eats everything in his sight and shoots fireballs from his mouth.
- Petey Piranha - The evil goop monster that is appointed a leader in the army by Super Piranha. He shoots sludge and can somehow fly. He is banished to the tropics by three of the star children.
- Kammy Koopa - A temporary squatter in the Mushroom Castle. She is puts up a fight when three star children attack her for being a squatter.
- Tatanga - He invades and attacks Sarasaland after Super Piranha has already wiped it out. He is very cowardly and is defeated once again by the star children.
There is indeed another sequel Diaper Duty 5: Koopa Kid Gets Mad.