In the year 2199, Earth is ravaged by attacks from alien beings of the the planet, Gamilus, which have devastated the surface of the Earth and forced what remains of mankind to take shelter underground. To save the Earth, the last of the Earth's space forces must distract the Gamilan forces while a non-Gamilan ship, the Amaterasu, lands on Mars to deliver the Wave Motion Activation Core to the Earthlings. While Captain Mamoru Kodai contains the enemy attack to allow fellow captain Juzo Okita to escape with his forces, Mamoru's brother Susumu and his friend Daisuke Shima investigate the Amaterasu that crashed on Mars. Inside the ship there is the corpse of an alien female, the messenger sent to Earth to make the important delivery to the Earthlings. Susumu and Daisuke return to Earth on the Kirishima, the only ship to return from the battle at Pluto. On the Kirishima, Susumu learns of his brother's death. When the Kirishima reaches Earth, Susumu Kodai looks for Captain Okita to know whether his brother was a decoy or not and meets Yuki Mori, who directs him to the hospital wing. Kodai confronts Okita, who says that it was he who led Mamoru to his death.

Susumu brings the Wave Motion Activation Core to Earth which allows mankind to complete its first interstellar spaceship, the "BBY-01 Yamato". With Okita as the captain, Shima as the navigator, and Susumu as its battle chief, the Yamato is assigned to travel to planet Iscandar, in the Great Magellanic Cloud, with orders to retrieve a device able to restore Earth's environment. Before the Yamato can start its journey, it must counter a Gamilan interplanetary ballistic missle aimed at them.

On Pluto, Gantz suggests sending out a fleet after the Yamato. Schultz turns down the suggestion, preferring to see what the Yamato does before attempting anything. After making a space warp, the Yamato 's main engine isn't transferring energy correctly, so Captain Okita orders the Yamato to land on a floating continent orbiting Jupiter, to make repairs to the engine. On the floating continent, Captain Okita orders the crew of the Yamato to go out and collect samples from the continent. After analyzing some of the plant samples from the continent, XO Shiro Sanada discovers that the floating continent is artificially made by the Gamilans. Meanwhile Raleta, commander of the Gamilas resupply base on the floating continent, gets a message from Gantz, ordering him to dispatch the combat fleet of four ships to attack the Yamato. The Yamato destroys three of the four ships sent after them, and then takes off from the continent. Okita orders Kodai to test fire the Wave Motion Cannon at the floating continent. Kodai fires the gun, destroying the entire continent. Nanbu is thrilled at the power of the weapon, but Okita says that the Yamato 's weaponry is for self-defense only, questioning whether they have done the right thing.

When the Yamato lands on the Saturnian moon of Enceladus to collect some cosmonite and to answer a distress call, Susumu, accompanied by radar operator Yuki Mori and a medical team, investigates the remains of a crashed Earth ship, which he finds to be his brother's vessel, the Yukikaze. Unable to find any clue about Mamoru's whereabouts, they are ambushed by androids sent by the Gamilans and must fight them to escape.

Before leaving the Solar System, the Yamato launches an attack to destroy the Gamilan facilities on Pluto to stop their bombardment of Earth with planet bombs. However, the ship ends up falling for a surprise attack from the enemy's secret weapon, and the crew of Yamato sends their pilot squadron to shut down the Gamilan base.

Having deceived their enemies who believe that the Yamato was destroyed for good, the crew takes the opportunity to stage a counterattack after the Yamato pilots find the location of the main base.

One of the Gamilan androids retrieved by the Yamato on Enceladus is reassembled and activated in an attempt to learn more about their enemies. Analyzer, the Yamato's own robot, makes contact with the android and manages to befriend it. However, when the android escapes its confinement, the rest of the crew enters a state of alert and searches for it.

The Yamato falls into a dimensional rift and finds itself unable to escape. A Gamilan ship that is also trapped there approaches the Yamato and both crews come to a temporary ceasefire while they work together to escape. After the Yamato escapes the dimensional rift, General Goer meets it with a Gamilan fleet. Instead of fighting the fleet, the Yamato runs away, and the dimensional rift temporarily widens, swallowing the fleet.