Natural Selection 2 is a dynamic first-person shooter featuring multiplayer battles in a futuristic setting. The opposing sides of the second part of the franchise are humans and alien creatures, who have been fighting for quite some time. Both factions crave the complete destruction of the enemy, which will make it easier for them to control outer space.

In addition to the shooter part, the project invites gamers to show their strategic skills when arranging their own base with the help of defense structures. Their proper placement will help protect against the enemy in the active phase of the battle, after both sides of the conflict have completed preparations. The commanders of the people and the Kharaa race constantly monitor the battlefield from above, and actively help their own thanks to a list of commander skills that differ depending on the faction, for example, teleportation of first aid kits and ammunition to allies and many others. The rest of the players take part in brutal skirmishes on vast maps with many passages and ways to get around their opponents.

Playing as aliens is different from the usual shooter. Gamers are invited to choose one of 5 alien options (Skalk, Gork, Lerk, Fade and Onos), which differ in speed of movement, size, armor, damage and more. To win in each of the available modes, you must fulfill several conditions based on team interaction.