After Numbuh 4 from the KND was sent to St. Rita's Preparatory School by his parents, Margie presented herself in her disguise as Principal Margaret, welcoming Numbuh 4 to the school, and went with him to his new class. Once at the class, Numbuh 4 came to the conclusion that all the students were girls, so Principal Margaret revealed to him that St Rita's was a school for girls, and subsequently, revealed her intentions to turn Numbuh 4 in a girl with her Girlifying Rifle. She just made Numbuh 4's hand to turn into a woman's, but Numbuh 4 used the powder from the speckles of the slate to escape. After became furious of Numbuh 4's escape, Principal Margaret made a tantrum and later left the classroom to went to her office at the school's tower, but she told her students to continue with their lessons, which they did not do as soon as she left, they started to play.
Once at the school's tower, Principal Margaret communicated with her future self Madame Margaret, who told her that she was busy at the moment and to just leave her a message. Principal Margaret left a message explaining her future self about Numbuh 4's escape, but Numbuh 4 appeared at the window and swinging with a lamp, launched against Principal Margaret and knocked her. Much to Numbuh 4's horror, he realized that he had "killed" Principal Margaret by splitting her in half, leading Margie to emerge from the robotic legs she was using to impersonate Principal Margaret and insult Numbuh 4 for breaking her disguise. While Margie and Numbuh 4 argued about Margie's plan to turn every boy into a girl, Principal Margaret's robotic torso, which was still alive, managed to get where the Girlifying Rifle was and tried to turn Numbuh 4 into a girl one last time, but Numbuh 4 managed to turn down Principal Margaret's robotic torso once and for all and broke the Girlifying Rifle in half, much to Margie's chagrin. To his bad luch, Madame Margaret appeared as a hologram to aide Margie, so she send four members of her Girl Squad, who managed to girlifie Numbuh 4's t-shirt into a dress, with Numbuh 4 escaping with his jetpack. However, they managed to girlifie Numbuh 4's jetpack into a woman's purse, which made him to fall to the ground. Subsequently, Margie activated the robotic legs of St. Rita's Preparatory School, chasing Numbuh 4, who was unable to call for help as Sector V was girlified.
75 years later, it's revealed that Numbuh 4 somehow escaped from the young Margie and went into hiding, but as a result, Madame Margaret became the supreme ruler of the world, sending her Girl Squad to girlifie or harass every living boy. However, Numbuh 4 created a resistance division named the Boys Next Door, who lived to fight against Madame Margaret and her tyranny. Feeling furious about the BND, Madame Margaret decided to create a giant and new version of the Girlifying Rifle known as the Supergirlifier Cannon, but it was still unoperational. Preparing for the ultimate battle against Madame Margaret's Girl Army, the BND were helped by Sally Sanban, Numbuh 3's granddaughter and a deserted member from the Girl Squad, who wanted to help the boys defeat Madame Margaret from extinct every boy in the Earth. Numbuh 4 dismissed her immediately, but he accepted her after she gave them a Girlifying Rifle to reverse its effects and make it a Boylifying Rifle. The rifle's effects were succesfully reversed. Meanwhile, Madmae Margaret revealed to her girls that she anticipated Sally's desertion and secretely planted a tracker on her to discover the BND's headquarters. Ready to extinct boys from the face of the Earth once and for all, Madame Margaret activated the robotic legs of St. Rita's Preparatory School, now her utopia's castle.
Once in front of the BND's headquarters, Madame Margaret ordered the BND's Leader to call the BND to face her Girl Army. Immediately, the BND emerged with their jetpacks and started to fight. Numbuh 2's descendant transformed two girls into boys, but Madame Margaret resolved to reveal that the Supergirlifier Cannon was now operational, destroying the BND's headquarters and transforming many of its members into girls. Although Numbuh 5's descendant came to the conclusion that they needed to abandon the battle to fight another day, the BND's Leader reminded him that Numbuh 4 and Sally needed more time to infiltrate St. Rita's, so Numbuh 2's descendant sacrificed himself to get them more time, only to be soon girlified along Numbuh 5's descendant and other members. Now alone, the BND's Leader resisted to became a girl, but Madame Margaret shot the Girlifier Cannon to him, transforming him into a girl. Glorious for her victory, Madame Margaret returned to her office, happy that she had now transformed every boy from the world into a girl, but Numbuh 4 appeared at the window and swinging with the lamp, he launched himself against Madame Margaret to knock her, mimicking their first confrontation 75 years ago. After Madame Margaret asked him what he was going to do, he revealed that he was going to call for help. She reminded him that the boys were no more on the Earth's face, but Numbuh 4 used her time machine to remind her that there are still boys in the past that could help him. After Numbuh 4 dissapeared, Madame Margaret went to the time machine to follow him and prevent his actions, but Sally appeared and crushed with her feet the time machine. Realizing that her fate had been sealed and this time there was no chance for escape, Madame Margaret screamed in horror knowing that everything around her including herself will promptly cease to exist.
When he returned to the past, Numbuh 4 warned the KND about the young Numbuh 4's situation before they were girlified by Margie, so they went with him to St. Rita Preparatory School, which had started to chase Numbuh 4. They saved Numbuh 4 and Numbuh 3 went to the battlefield with the H.I.P.P.I.E. H.O.P. to face Margie's Girl Squad. Margie ordered the Girl Squad to destroy the H.I.P.P.I.E. H.O.P., but after shooting against it with no effect, Margie realized that the H.I.P.P.I.E. H.O.P. was too girly already to be affected by the Girlifying Rifles. Subsequently, the H.I.P.P.I.E. H.O.P. entered into her office, scaring the Girl Squad away and roaring at Margie. With one last card up her sleeve, Margie attempted to call the still existing Madame Margaret to get help from her and avoid defeat, but Numbuh 3 crushed the time machine with her feet mimicking the way in which her future granddaughter defeated Madame Margaret in the future, effectively sealing the fate of both Madame Margaret and the Girl Squad. Numbuh 3 then arrested Margie and under Numbuh 1's orders, she was send to the Kids Next Door Artic base to pay for her crimes. Following her arrest, the future Numbuh 4 faded into oblivion and the Girl Squad was erased from existence, as well St. Rita's Preparatory School crashed down.
75 years later, on those same grounds in which St. Rita's was destroyed, instead of Madame Margaret's dystopian girly future, there is a playground built for boys and girls, strongly implying that Margie likely spend the rest of her days in prison or is still at prison, precluding her to carry out her evil plans.
Margie was teased by her brothers resulting her in having an anti-male militant feminist personality and has a strong hatred of males. She uses a robotic suit to hide her true form and uses time travel to get technology and resources to rid the world of the male population. Underneath her female supremacist persona, she acted more like a whiny spoiled brat being easily irritated and acts very childish when not attempting to purge the world of men.
- Her beliefs and tactics are similar to Adolf Hitler, both believing that one specific group (race for Hitler, biological sex for Margie) was superior to others, both wanting to murder anyone in any specific group that they hate, and both leading powerful militiant forces. Her being paraplegic makes these similarities ironic, as Hitler and the other Nazis also hated disabled people.
- Her beliefs, tactics and physical appearances are similar to Mrs. Tweedy, both believing that one specific group (species for Melisha, biological sex for Margie) was superior to others, both wanting to murder anyone in any specific group that they hate, (For Margie's case is Boys, while for Melisha's case is Chickens), and both leading powerful militant forces. Her being a child, who wears glasses and bullied by her brothers makes these similarities ironic, as Mrs. Tweedy from Chicken Run is an adult, who never wears glasses and married to the male farmer called Mr. Tweedy.
- Her beliefs and tactics are similar to Lord Farquaad, both believing that one specific group (race and species for Farquaad, biological sex for Margie) was superior to others, both wanting to murder anyone in any specific group that they hate, (For Margie's case is Boys, while for Farquaad's case is Fairy Tale Creatures and Ogres), and both leading powerful militant forces. Her being a female child makes these similarities ironic, as Lord Farquaad from Shrek in a male adult.
- Her hatred of boys is similar to Numbuh 86 but to a greater more extreme extent.
- Her plans to turn every boy in the world into a girl is a very, very fatal one. Without any males, there would be no way for women to reproduce, ultimately leading to the human race going extinct from a lack of new generations. It's probable that Margaret did not know this or she didn't care about this. Alternatively, it may be possible that she left some males alive for her amusement or that her girls were clones.