In the year 2220 A.D., the Earth Federation launches a plan to evacuate Earth when discovering that a traveling black hole capable of destroying anything in its path is on course towards the solar system. As the people on Earth prepare to relocate to planet Amare, whose ruler offers refuge, the tyrants known as the "S.U.S. Empire" attack the first Earth evacuation fleet. After learning that his wife Capt. Yuki Mori-Kodai disappeared in the battle and that legendary space battleship Yamato has been fully rebuilt, Susumu Kodai accepts command of the ship as he intends to not only help humanity once again, but also find Yuki in the hope of helping his relationship with his daughter Miyuki, who puts the blame on him for her mother's disappearance. But in order to fullfil the mission, the Yamato must go through battles against the SUS Empire, who intend to spoil humanity's hopes of finding a new place to live in and turn Earth into energy for their own selfish needs.

In the galactic group there are more than 100,000,000,000 galaxies, and the Milky Way galaxy, the one which includes Earth's solar system, is only one of these... one of many in the immensity of outer space. This story starts in the year 3199, when a mighty enemy attacks the Milky Way from a neighboring galaxy. The enemy engages the combined forces of the Milky Way, an Alliance of many stellar nations, and defeats them one after another. The remaining Milky Way Alliance forces are reduced to just six fleets. After the Alliance headquarters is destroyed, and when the collapse of the central Milky Way Alliance is imminent, the Great Yamato Zero surprises everyone and embarks on a mission to assist the Milky Way Alliance in one last great battle.