E.V.O. tells the saga of life's evolution on Earth, with a subtext of a creation myth and polytheistic evolution. The player takes the role of one of many billions of lifeforms created by Gaia, the nurturing and benevolent daughter of Sol, the Sun. Among the creatures known as life, there is a competition to evolve, and the best lifeform will eventually be granted the privilege of entering the Garden of Eden and becoming the husband and partner of Gaia. As the game progresses, it soon becomes apparent some mysterious external force is interfering with evolution on Earth in a destructive manner. Strange crystals not native to Gaia appear across the planet, and creatures that eat the crystals are transformed into monstrously powerful beings that dominate all other lifeforms, overconsume resources and disrupt the flow of evolution. In each Age the player character is tasked with confronting the species transformed by the crystals and defeating them so that the evolution of life can continue as intended.
In the final Age, the Age of Eden, the player learns a mysterious entity is controlling the world's other lifeforms and sending them against the player. This entity turns out to be Bolbox, a lifeform that has evolved into a freakish and evil advanced being by consuming the crystals, believing itself to be the first human, but in reality is a gigantic single-celled organism. In the game's final battle, the player and Bolbox fight to determine who will gain entry into Eden and become Gaia's partner. Bolbox is defeated, and the player joins Gaia in Eden and is granted the gift of intelligence. It is also revealed the crystals were introduced to Earth by an advanced civilization on Mars, who misguidedly wished to help Earth by speeding its evolution with the crystals. Upon realizing the dangers the crystals create, the Martians decide to leave Earth alone and observe until it becomes advanced enough for them to interact with.