In the year 2199, the planet Earth is on the brink of annihilation. For five years, humanity has been under relentless attack by the alien Gamilas Empire, which has bombarded the planet with radioactive meteorite bombs, rendering the surface uninhabitable and forcing the surviving population to flee to vast underground cities. With the radiation seeping ever deeper, scientists estimate that the human race will be extinct within just one year.

Hope arrives from an unexpected source. A former Earth Defense Force pilot named Susumu Kodai, living as a disillusioned scavenger, discovers a mysterious message capsule on the surface of Mars. The message comes from Queen Starsha of the distant planet Iscandar. She offers humanity a device known as the Cosmo Cleaner D, which can completely remove the deadly radiation from Earth’s atmosphere. However, Iscandar is located 148,000 light-years away in the Large Magellanic Cloud, a journey far beyond the reach of conventional space travel.

The message also contains blueprints for a revolutionary technology: the Wave Motion Engine, a propulsion system capable of faster-than-light travel. Desperate to save their world, the United Nations of Space Administration secretly begins an ambitious project. They raise the remains of the legendary World War II battleship Yamato from the ocean floor where it was sunk and rebuild it into a colossal interstellar spacecraft. The newly christened Space Battleship Yamato is equipped with the Wave Motion Engine and a powerful, secret weapon—the Wave Motion Gun, capable of unleashing devastating energy.

Susumu Kodai, still haunted by the death of his brother and parents in the Gamilas attacks, initially resists rejoining the military. However, he is ultimately persuaded to join the Yamato's crew. Under the command of the stern but dying Captain Juzo Okita, the ship and its 114 crew members launch on a desperate one-way mission to retrieve the radiation-cleaning device and return to Earth before the one-year deadline expires.

The voyage to Iscandar is perilous. The Yamato must navigate the vast expanse of the galaxy while constantly evading the formidable forces of the Gamilas Empire, whose leader, the ambitious and ruthless Leader Dessler, is determined to prevent the ship from reaching its destination. Dessler dreams of conquering Earth and sees the Yamato as a direct threat to his ambitions. The crew faces a series of harrowing encounters, including battles with Gamilas fleets, navigating treacherous space phenomena like dimensional rifts and the Rainbow Galaxy, and confronting powerful enemy commanders such as the brilliant General Domel and the desperate commander Schultz on Pluto.

As the journey progresses, Kodai begins to mature from a bitter, hot-headed young man into a capable leader. He develops a deep bond with Captain Okita, who sees in him the son he lost in battle, and a close working relationship with the ship's operations officer, Yuki Mori. The Yamato survives numerous close calls, often relying on the courage of its crew and the overwhelming firepower of its Wave Motion Gun to break through impossible situations.

In the final act, the Yamato successfully reaches Iscandar and receives the Cosmo Cleaner D from Queen Starsha. However, the mission comes at a great cost. Captain Okita succumbs to his illness, passing away just as the ship returns to Earth orbit. Furthermore, the victorious return is short-lived, as a final, crippling attack from a surviving Gamilas warship leaves the Yamato severely damaged and a massive missile heading toward the planet. In a climactic act of self-sacrifice, Susumu Kodai orders the remaining crew to abandon ship. He then pilots the crippled Yamato on a collision course with the missile, destroying it in a massive explosion that saves Earth. The ship and its captain are seemingly lost, but the Cosmo Cleaner D is successfully deployed, beginning the long process of restoring Earth's surface to a life-sustaining state.