The futuristic city of Omikron on the planet Phaenon is sprawling beneath a huge crystal dome. It was erected to protect the city against the ice age which descended upon the planet after its sun ceased to exist. At the beginning of the game, the player is contacted by an Omikronian police officer named Kay'l 669, who begs him to leave his dimension, possess Kay'l's body, and enter Omikron to investigate a series of strange murders. The player then takes the role of Kay'l, but his investigation is foiled by a sinister force that the police are unable - and perhaps unwilling - to stop. As the plot unfolds, the player realizes that in order to solve the mystery his soul must establish contact with many inhabitants of Omikron, and ultimately save it from extinction.

Omikron: The Nomad Soul is primarily a free-roaming third-person 3D adventure game. Much of the player's activity in the game consists of exploring the large city, which is separated into five districts. The player is generally free to roam the city regardless of the plot development. Certain buildings can be entered and explored. Automatic taxi-like vehicles called "sliders" can be hailed to shorten walking distances and deliver the protagonist straight to the goal. In order to advance the story, information must be gathered by communicating with characters and solving puzzles of various kinds, inventory- as well as logic-based. The emphasis of the gameplay, however, is on exploration and interaction rather than on puzzle-solving.

Throughout the course of the game, the player may take on the role of up to 41 different characters through the use of the soul transfer ability. In many situations, a soul transfer is required to solve a puzzle and advance the plot, e.g. accessing a restricted area with a specific character who is able to enter it without arousing suspicion.

Besides the adventure mode, the game also contains first-person shooter and fighting gameplay. These two modes are restricted to specific areas and are for the most part triggered by plot advancement. Once an FPS sequence has been initiated, the player must complete it in order to be able to return to the main adventure mode. Weapons and items for this mode can be found throughout the stages themselves, as well as bought in shops during exploration.

The fighting sequences are also usually dictated by the plot. They take place on side-scrolling screens and consist of traditional exchanges of punches and kicks, with the goal of depleting the opponent's health bar. Each character has different initial fighting statistics. These can be increased by taking the characters to a training facility and practicing to increase their parameters and subsequent combat performance.