Yoshino Takigawa, an ordinary teenager, is secretly dating his best friend Mahiro Fuwa's younger sister, Aika. But when Aika mysteriously dies, Mahiro disappears, vowing to find the one responsible and make them pay for murdering his beloved sister. Yoshino continues his life as usual and has not heard from Mahiro in a month—until he is confronted by a strange girl who holds him at gunpoint, and his best friend arrives in the nick of time to save him.

Yoshino learns that Mahiro has enlisted the help of a witch named Hakaze Kusaribe to find Aika's killer. However, the witch has been banished to a deserted island due to infighting within her clan. Hakaze's brother, Samon, selfishly desires to make use of the Tree of Exodus' power, in spite of both his sister's opposition and the impending peril to the world. With Hakaze out of the picture, it is now up to Yoshino and Mahiro to help her save the world, all while inching ever closer to the truth behind Aika's death.

Zetsuen no Tempest draws heavily on two Shakespeare plays, Hamlet and The Tempest.