In the year 2194, The Gamilas, an unknown enemy began invading the Earth. In response the nations of the Earth pooled their resources to fight back, but they were ultimately defeated and much of humanity had been wiped out.

Five years later, in 2199, the Earth having been severely polluted by meteor bombs, led what was left of humanity to flee underground. One of the few left alive was a former pilot, Susumu Kodai, and while one day he is exploring above ground, a mysterious object falls from the sky. As it turns out it is a communications capsule from the planet of Iskandar, 148,000 light years from Earth. Apparently Iskandar has sent a message describing equipment that can eliminate the radiation as well as the location of Iskandar, and plans for a "wave-motion engine" that can help them travel the distance very quickly.

The Defense Force of Earth equips the Space Battleship Yamato with the "wave-motion" propulsion system to undertake the mission, which is also supported by Captain Okita, to retrieve the device. Kodai after hearing of this as well as a call out from the Defense Force for volunteers, rejoins the Force to set out with the Yamato.
Now the fate of the Earth is in their hands, the crew of Yamato blasts off for a distant Iskandar. They have
one year until radiation drives humanity to extinction, Yamato is now humanity's last hope for survival!