The Familiar of Zero follows the adventures of the protagonists Louise and her familiar Saito. Louise is a second year student at the Tristain Academy of Magic. In this world, those who can use magic are either mages or nobles.

Louise is terrible at magic, and can never use it the way she wants to. She is given the nickname "Louise the Zero" by her classmates, due to the inability to use any of the four common magic elements, whereby a mage's power is determined by the number of elements they can use ranging from a single element, one (dot mage), two (line) three (triangle) and four (square). Early in the school year, the second year students summon their familiars; this is considered a special ritual where a mage summons their eternal protector and partner, which usually is some sort of magical creature. Louise manages to summon a human commoner named Saito Hiraga, leaving her totally humiliated. Due to the sacredness of the ritual, Louise is left with no choice but to reluctantly accept Saito as her familiar. She proceeds to treat Saito as any other familiar only worse, making him sleep on a bed of hay and beats him with a whip for little to no reason, among other things.

One day Saito challenges a noble who disrespects commoners (Guiche) to a duel. Saito is beaten badly at first, but once a sword was put in Saito's hands, he gained a mysterious power and with this power he is able to defeat the noble in the duel. Louise and Saito's relationship's develop during the course of the story. Together they face many mysteries and uncover unexpected truths, including the nature of Saito's mysterious power, and the truth behind Louise's inability to cast magic.