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.

Five dangerous "seeds" have been stolen from their vault in the world of Evergreen and taken to Earth. Natsuki, an agent of the Queen, has been sent to retrieve them. However, he cannot do this alone and enlists the aid of Chihaya, a middle school student, who is "the only one" who can help him. With his aid she transforms into Magical Warrior Carmine in order to save the humans possessed by the seeds. Questions abound though, such as why Chihaya's mother appears to know all about this secret activity, why Chihaya remembers her father who reportedly died before her birth, and why she dreams of Evergreen, which she has never seen.

In the land of Terra, natural disasters of unknown causes have been occurring irregularly in many areas. Therefore, the majority of the people, in order to escape those natural disasters, came to live in mobile cities developed over the years. The Originium left behind at the site of such Catastrophes, has led to the rapid progress of civilization due to their immense energy. But it also brought something else with it — an incurable disease called Oripathy. Because the bodies of those with Oripathy gradually crystalize and become a new source of infection at the time of death, in many countries, the Infected are subject to persecution under regimes of segregation and forced labor. Those who were oppressed by the governments are starting to rebel. Rhodes Island, a pharmaceutical company researching a cure for Oripathy, takes up their arms and starts a conquest trying to save all the people from the disease.

Despite having a good reputation as one of the most seasoned guards in the local guild of Mebuki, Kikuru Madan believes he has been wasting his youth and hopes to spend the rest of it like any other person. However, his conscience prevents him from retiring at present, as he worries about the guild's future without him. Coincidentally—as if to help him find his successor—the guild's receptionist, Enome, assigns Kikuru four fresh recruits: the energetic beastwoman Hitamu "Hitamuki" Kyan, the prodigy Maidena Ange, the laid-back Toxico Dannar, and the stalwart Hanabata Nohkins. Although each of them possesses significant talents, they also display characteristics that detract from their potential—including Hitamu's extreme clumsiness and Hanabata's unintentional perverseness. As if there was not enough to deal with, the monsters outside Mebuki's walls start exhibiting odd behavior by targeting women salaciously, causing the party endless problems in more ways than one. Nevertheless, Kikuru is committed to retiring early; to achieve his goal, the guidance he gives the trainees will be absolutely essential.