When vile aliens known as the Gamilons wreak nuclear havoc on Earth, a group of survivors refit the Japanese battleship Yamato for intergalactic travel and set off on a mission to retrieve a neutralizer that will eradicate the radiation from Earth's atmosphere.

The Galman Empire is destroyed but the planet Galmania is not, by a chance collision of galaxies. The Bolar Federation worlds including Planet Bolar are destroyed. The Yamato, back under the command of Captain Okita, encounters the planet Denguil too late to save its humanoid civilization from being flooded by the water planet Aquarius. The surviving Denguil, a warrior race who believe only the strong should survive, plan to use Aquarius to flood Earth and destroy humanity, in order to create a new home for their race.

Time to ease up ... not! Although the Yamato's crew has witnessed the end of the long, hard-fought Comet Empire War, a peaceful future will have to wait. While Dessler gathers together the shattered remnants of his Gamilus Empire, new forces are at work in the universe that could augur in another conflict. Seems the Black Star Empire has invaded Dessler's homeworld and is decimating it, all the while gathering power for its war machine.

In the year 2220 A.D., the Earth Federation launches a plan to evacuate Earth when discovering that a travelling 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.

The Black Nebula Empire attacks Earth and threatens to blow up the planet with a bomb they placed on Earth if counter attacked. Earths hopes rest on the Yamato crew as they go to the Black Nebula Planet and try to find a way to difuse the bomb before it's too late.

The Yamato and her crew face the onslaught of the Comet Empire, a civilization from the Andromeda Galaxy who seek to conquer Earth, led by Prince Zordar. They have harnessed a comet and is using its terrible power to unleash destruction upon its rivals and inferiors... which are in fact everyone. The Space Battleship Yamato heads back into action. But this time, it shall not return, and much of the Yamato crew have signed on for their last voyage.