While taking a ferry to Fuuka Academy, new students Mai Tokiha and her sickly younger brother, Takumi, spot a girl adrift on the water. Shortly after bringing her aboard, the ferry comes under attack from an assailant who summons a mechanical monster. Despite still recovering from her injuries, Mikoto Minagi fends off the monster using a supernatural sword. Mai soon discovers that Mikoto is a fellow Fuuka Academy student with abilities called HiME (Highly-advanced Materializing Equipment). Female students with HiME are responsible for defending the academy and the local city from the monstrous "Orphans." After several incidents at the school involving battles against these mysterious creatures, Mai learns that she is a HiME herself and is capable of summoning a Child, a mechanical creature capable of great utility and firepower. Now burdened with new responsibilities, Mai joins 12 other HiME as they safeguard the school from a threat they know little about all while protecting the ones closest to them.

Mai-HiME was released on DVD in Japan from January 28, 2005, to September 23, 2005. Bandai Entertainment published the series in North America in seven DVD volumes from March 28, 2006, to April 3, 2007. A remastered Blu-ray and DVD collection was released by Funimation on January 9, 2018. The anime was adapted into multiple video games for the PlayStation 2, PlayStation Portable, and Windows PC.