Maria†Holic follows Kanako Miyamae, who transfers to Ame no Kisaki Catholic School after becoming convinced that the place where her parents first fell in love might also be where she can finally find her own romance. Unfortunately, Kanako has one major obstacle: men make her break out in hives, so she arrives at the all-girls academy determined to find a partner of the same sex.
There she meets the dazzling Mariya Shidou and immediately believes she has found the girl of her dreams, only to discover that Mariya is actually a cross-dressing boy. Mariya promptly uses that secret to blackmail Kanako, threatening to expose her supposedly impure intentions unless she helps keep his real gender hidden. He even replaces Kanako's original roommate so he can keep a close eye on her at all times.
Against the strict routines and relentless gossip of an elite girls' school, Maria†Holic turns Kanako's search for love into a chaotic struggle of secrets, misunderstandings, and forced proximity as she tries to survive life with Mariya while still chasing the romance she came for.