Long ago, a bird-like race of creatures (called the Chozo) became extremely advanced technologically, but due to increasing violence in the universe, they began to hide and live more simple lives. The planet Tallon IV was the site of one of their colonies. Years later, a meteor crashed on Tallon IV releasing the strange element Phazon into the planet. Phazon poisoned anything it came in contact with, causing the plant and animal life to either die or mutate into a hideous form.

The Chozo tried to control the power of Phazon but failed. Before abandoning the planet, they were able to cover the impact crater with a temple and seal Phazon into the planet's core. Now space pirates have discovered Tallon IV, moving in to study Phazon and harnessing its power. They have also begun rebuilding their fortress on planet Zebes and reviving the Mother Brain, Ridley, and Kraid, all of whom were destroyed by Samus Aran. However, Samus has tracked the space pirates to Tallon IV and must now enter the planet to destroy them once and for all before they have a chance to rebuild their destructive forces...

Metroid Prime is a change from the platform-adventuring series, entering the first-person shooter genre for the first time. Players are now behind Samus Aran's visor and must use all their resources to investigate the pirate infestation of Tallon IV. Players can use Samus's beam, with missile and charge capabilities. Along the way, they must recover the bounty hunter's lost abilities like the morph ball and grapple beam, which allow them to reach unexplored areas of Tallon IV. Players must piece together the story of the fallen Chozo to figure out what has happened to the poisoned planet and prevent the pirates from using the Phazon to wreak havoc throughout the planets.