Schoolgirls discover that they have been given the ability to materialize weapons and control robotic beasts called "Children" to stop an evil organization from their plans of domination.
Mai Tokiha and her brother Takumi are on a boat trip when a girl with a sword, Mikoto Minagi, is found in the water. They pull her aboard, but are attacked by Natsuki Kuga. The boat is destroyed in the battle between Mikoto and Natsuki, and Mai shows strange abilities.
Mai and Takumi go to their first day at school. Mai skips class and bonds with Mikoto over a bowl of ramen. Takumi is attacked by a monster, and Mai and Natsuki put aside their differences to fight it.
Mai calls forth Kagutsuchi and defeats the Orphan Later, Mashiro Kazahana explains to Mai that she is a HiME and that she is needed to fight Orphans. Mikoto becomes Mai's roommate.
Little Orphans are stealing lingerie from the girls at school. Natsuki must walk around without underwear on a windy day, to her chagrin. Using Natsuki's underwear collection, they lure the Orphans and destroy them.
An Orphan is attacking city buses, but Mai has her own problems. The stress of taking care of her ailing brother gets to her, and Yuuichi Tate comforts her in the rain. They later go back to teasing one another.
Yuuichi and Shiho Munakata enlist Mai, Takumi and Mikoto to help them prepare for a wedding. Shiho worries that Yuuichi likes Mai, and makes Mai root for her love of Yuuichi. Midori Sugiura turns out to be a HiME and ends up as a teacher at the school.
Mikoto falls under the influence of Nao Yuuki. Nao shows Mikoto how to lure men by posing as underage prostitutes, then use their powers to rob them. Mikoto has second thoughts, and the other HiME put a stop to it.
The school holds a festival. Akane Higurashi fights an Orphan to protect her boyfriend Kazuya, but Miyu Greer kills Akane's Child, and Kazuya dies. Nagi Homura explains that the life of the person who's most important to the HiME is forfeit, not the HiME's life as Akane thought. Mai fights with Kagutsuchi for the second time, and reveals her powers to Reito.
Mai's relationships with Reito Kanzaki and Tate continue to develop. Natsuki takes Mai and Mikoto on an information gathering mission at an abandoned First District building. Natsuki eplains she's trying to destroy the First District.
Mai and her friends have their cake baking contest organizaed by Midori Sugiura but the contest is interrupted by an Orphan. Takumi is attacked by another Orphan and it turns out Akira Okuzaki is a HiME — and a girl. She saves Takumi, who throws a birthday party for Mai.
A vampire is stalking the campus. It removes girls' clothing and drinks their blood trying to determine if they are HiMEs. Nagi tells Mai not to get involved with it, since there appears to be another group looking to use the HiME. The school's nun, Yukariko Sanada, turns out to be a HiME and defeats it.
Joseph Greer, Miyu, and Alyssa Searrs are working for the Searrs Foundation. They kidnap Natsuki, and Yukino Kikukawa, who is a HiME, uses her powers to find her. Mai and Mikoto go to rescue her, and save her from Miyu and Alyssa Searrs. In the end, Alyssa takes over control of the operation from Greer.
The school hosts a romantic festival, and Mai and Reito go on a date. They are about to kiss when Tate interrupts, angering Shiho. Alyssa and Miyu test out Alyssa's powers, and Natsuki investigates the First District.
Alyssa destroys a bridge with a shot from heaven, and the Searrs group sends in its personal army and takes over the school, looking for HiMEs. Nagi and Mashiro then gather the HiMEs in an underground cavern.
The HiMEs defeat the Searrs soldiers and rush to confront Alyssa. Alyssa attempts to destroy the school (and students) with a blast from her Child, but Mai intercepts the beam with Kagutsuchi, seemingly killing her. Alyssa and Miyu escape, but Joseph Greer shoots Alyssa and Miyu kills him.
Mai shows up late for class, to Mikoto's delight. Midori organizes the HiMEs into the HiME Rangers, and takes them out to karaoke to bond. Takumi discovers Akira's true identity and she must kill him. Afterwards, Nagi tells them that there will be no more Orphans; now they must fight each other's Children. The HiME's Carnival had just begun.
Nagi informs the HiME Rangers that an evil star is coming, and the only one who can save the world is the HiME who defeats all other HiMEs. Tate tells Mai that he must stay with Shiho, because he caused her to be injured. Takumi is accepted for a transplant at a US hospital.
A mysterious flute-playing HiME attacks Mai. Mikoto protects her, but Mai tells her not to fight. Yukariko betrays the group, and causes Natsuki to fight Nao, saying Nao attacked her.
The HiMEs start to turn on each other; Yukino is blackmailed into attacking Mai. Takumi worries about being a burden to Mai, and makes plans to go to America alone. Akira grows more devoted to Takumi, putting him in danger. Shiho kisses Tate in front of Mai to hurt her.
A crow Child causes Mikoto to fight and kill Akira's child. Mai arrives in time for Takumi to evaporate in her arms. She and Mikoto then battle, while Mikoto flashes back to how her brother is the Obsidian Lord.
Nao attacks Natsuki, and Shizuru reveals herself to be a HiME while saving Natsuki. Meanwhile, Mashiro and Fumi go to confront the Obsidian Lord, who turns out to be Reito. Mikoto fights for Reito and defeats Mashiro and Fumi.
A large portion of the students are missing after the last battle. Haruka and Yukino look for Shizuru, and find her with Natsuki, who Shizuru has been inappropriately touching while she sleeps. Mai goes in search of the Black Prince to learn if killing the other HiME's Children will give her the power to bring back Takumi.
Midori wakes up Miyu with the key given to her by Mashiro. Mikoto tries to stop her, and Mai learns that Mikoto works for Reito now. Meanwhile, Shizuru defeats Yukino and Haruka evaporates. Yuuichi learns from Natsuki that Mai has feelings for him and goes in search of her.
Shizuru destroys Nao's Child, killing Nao's hospitalized mother. Shiho turns out to be a HiME and attacks Mai. Mikoto kills Shiho's Child, and Yuuichi evaporates as Mai tries to explain that she loves him.
Shizuru and Natsuki battle and then evaporate because of their love for each other. Miyu goes to kill the Obsidian Lord. Mai goes after the Black Prince as well, but Mikoto shows up to stop her with her Child.
Miyu wakes up Mashiro from a frozen block of ice. Mashiro then revives all the people who had evaporated. Mai and Yuuichi defeat the Obsidian Lord, and everything returns to normal. Reito and Yuuichi want Mai, and Mikoto doesn't want to share.