Apprentice mage Chise Hatori is invited to enroll at the College, a prestigious learning institution for sorcerers, to examine and look for a way to remove the curses she bears. Despite her groom Elias Ainsworth's reluctance, Chise accepts the proposal, as she believes attending the school might help her minimize her self-sacrificing tendencies. From the get-go, Chise grabs the attention of her classmates and professors alike, who have never seen a mage in action before. However, there is a sinister plot brewing behind the College's back, and the young mage will have to determine who is friend or foe in order to put a stop to it.

Hime Shiraki appears to have it all: an angelic voice, an innocent personality, and an adorable face that enamors all onlookers. However, her cuteness is all a lie—it is purely an act to achieve her self-centered goal of marrying a rich suitor. Though she often plays up her innocence to gain favor from those around her, Hime's facade does not absolve her of responsibility when an accident leaves Mai Koshiba injured. Learning that Mai is the manager of Café Liebe—a cafe themed as an all-girls academy—Hime is coerced into taking up a part-time position until Mai recovers. However, Hime's facade cannot cover up her shortcomings at being a waitress, earning her the ire of one of her coworkers, Mitsuki Yano, the elegant "onee-sama" who often berates Hime over her mistakes. As Hime struggles to adjust to her new job in addition to Mitsuki's unrelenting hostility, her real personality begins seeping through the cracks.

Megumin is a young and passionate wizard from the Crimson Demon Village, a remote community of mages with red eyes and a flair for the dramatic. She has devoted her life to mastering explosion magic, a powerful but impractical spell that leaves her drained of mana and unable to move for the rest of the day. Regardless, she refuses to learn any other skills. Along with her childhood friend and self-proclaimed rival, Yunyun, Megumin enrolls in the Red Prison: a prestigious academy for Crimson Demon magic users. There, she learns more about the secrets and history of her clan, as well as the threats and challenges they must face. As she polishes her power at the Red Prison with the help of her loyal familiar Chomusuke and her adorable little sister Komekko, Megumin aims to become the greatest explosion wizard of all time!

After a successful showdown at Tokyo Tower, the Mew Mew girls enjoy a temporary respite. Now that Ichigo Momomiya and Masaya Aoyama have confessed their feelings to each other, Ichigo is overjoyed to spend time with her new boyfriend. However, their quick break gets interrupted, and soon the girls must battle against the Chimera Anima yet again. When things go awry in the ensuing fight, Ichigo is placed in grave danger. Just when things look most bleak, the mysterious Blue Knight arrives and saves Ichigo, proclaiming that he was born to protect her, before disappearing into thin air. With the fate of the world on their shoulders and the identity of the Blue Knight in question, the Mew Mew girls must strive to create balance between alien-fighting and their personal lives.