Aliens from the planet Gamilas attack Earth with radiation bombs and reduce the lush planet into a wasteland with humanity forced underground. However, in 2199, a friendly alien race from the planet Iscandar contacts the humans and gives them the blueprints to build a powerful warship capable of retrieving a device, the Cosmo Reverse System, to cleanse the planet before humanity disappears. The United Nations Cosmo Navy – whose space fleets have been mauled by Gamilan forces – resurrects the long-sunken battleship Yamato and applies the alien technology to its interior, transforming it into the vessel for which the series is named: Space Battleship Yamato.
Over the course of the series, the Yamato and its crew are continuously harassed by Gamilan forces on Jupiter, the moons of Saturn, and Pluto. As the Yamato battles its way out of the Solar System and the Milky Way Galaxy, Gamilas leader Abelt Dessler takes a personal interest in the unusually advanced and seemingly unstoppable Earth vessel. Suspicious of Iscandar's involvement in the humans' quest, Dessler schemes to stop the Yamato at all costs before it can fulfill its mission - even as political intrigues plague his empire. To this end, he orders his top military commanders and most sophisticated spacecraft into the fight, putting the determination of the Yamato crew to even more rigorous tests as they cope with questions about their mission and strange incidents aboard their own ship.