Godzilla: Save the Earth takes place two years after Godzilla: Destroy All Monsters Melee. The story involves mankind getting hold of Godzilla's DNA, known in the game as "G-Cells." The Vortaak learn of this and once again return to Earth with a vast army of monsters, including their ultimate weapon: SpaceGodzilla. The player faces down many Vortaak controlled monsters in different locations across the Earth.

This time around, new monsters are added as well as more detailed arenas including hills, elevated highways, and waist-deep water. Another addition is Challenge Mode, in which the player must attain goals other than simply defeating their opponent