A thousand years into the future, Earth has been destroyed by powerful aliens known as Gauna. Although mankind has fled into space, the giant spaceships they now call home are still constantly being targeted by the strange creatures. Piloting mobile weapon units called "Gardes," humanity is able to take a stand against their adversaries by destroying their cores, preventing the monsters from regenerating their protective shell of placenta.

Within the vessel Sidonia, a boy named Nagate Tanikaze surfaces from its depths for the very first time in his life. With an incredible amount of time clocked into pilot simulators during his isolation deep within the ship, he quickly proves to be an indispensable asset to humanity's defense force. With the opportunity to pilot the legendary Garde Tsugumori, he fights to protect Sidonia from a grim demise.