Saito Hiraga and Louise Françoise Le Blanc de La Vallière go on the offensive after the events of Zero no Tsukaima: Princesses no Rondo. Together, they face off against King Joseph in the Holy City of Romalia with the help of two others who control the power of the “void”. But in the midst of the many conflicts ahead of them, an ancient evil begins to stir in the shadows. Will their close bonds blossom into something more or will they be shattered through the ever increasing difficulty of the tasks that they must undertake? Zero no Tsukaima F follows the story of Louise and Saito as they face their final challenges together.

Masahiro Setagawa is a hopeless teenager who is often used by the neighborhood bullies as an errand boy. Defenseless, Masahiro knows that nobody will ever save him. However, his life drastically changes when he meets Kousuke Ooshiba, a man known as the "Bear Killer," who takes down neighborhood gangs. A year later, Masahiro and his former friend, Kensuke Ooshiba, attend high school, only to find that Kousuke is their math teacher. While the three grow closer, Masahiro starts to view Kousuke as his "hero," and Kousuke develops an urging desire to protect Masahiro. However, their normal lives take a turn when Kensuke's childhood friend, Asaya Hasekura, returns, seeing Kensuke as more than just a friend, much to his surprise. Will the three boys be able to live a regular high school life? Or will forbidden love keep them apart forever?

For generations, the Bernstein family has been recognized as a house of nobles who favor books over everything else. Elianna Bernstein, daughter of a baron of the Sauslind Kingdom, is no different. But instead of being called a bookworm, she is known as the Bibliophile Princess. Four years ago, the crown prince, Christopher Selkirk Asherald, offered Elianna a special arrangement: if she would become his fiancée, he promised that she could continue to spend all her free time reading. Despite having to inherit a title of great responsibility, she agreed to the proposal, enticed by the prospect of gaining access to the royal archives housing a wide selection of books. To this day, Elianna firmly believes that her engagement is void of romantic sentiment. When she notices Christopher's interactions with another girl, she presumes that the days she spends with him will soon reach an end. Yet, during this period of uncertainty, Elianna and Christopher open a new chapter in their relationship, gradually uncovering their genuine feelings as they grow to better understand each other.

Third-year high school student Jirou Yakuin is in love with his childhood friend and classmate, Shiori Sakurazaka. Thus, he hopes to be paired with her for the "marriage practical": their school's practice of randomly selecting boy-girl pairs to live as pretend married couples while monitoring and rating them on how close they have gotten. Meanwhile, the lively Akari Watanabe wants to be assigned to her crush, the popular and good-looking Minami Tenjin. Much to their dismay, Jirou and Akari find out that not only have they been paired together, but so have Shiori and Minami! Determined to be with their crushes, Jirou and Akari strive to earn as many points as possible, as the top 10 pairs earn the right to switch their partners—so long as both couples agree.