Nihilanth is main antagonist and final boss of Half-Life Gordon Freeman is tasked with killing the Nihilanth as it is the only force holding the dimensional rift open after the Satellite Delivery Rocket launched by the Black Mesa Lambda Labs failed to reverse the Resonance Cascade. After Gordon enters Xen, the Nihilanth regularly contacts Gordon telepathically and occasionally taunts him. These messages are often received right after a teleportation in Xen.

Upon entering its lair, the Nihilanth attacks Gordon by launching two different types of energy spheres: a swarm of blue-colored electrical orbs which cause immense damage and have a small splash radius and a slow-moving, green-colored orb which homes in and teleports him to other sections of the Nihilanth's lair populated by other Xen aliens. In addition, these green spheres also teleport creatures into the Nihilanth's main chamber on impact with the cavern walls to help defend against intruders.

A series of gold-colored "energy spheres" orbit around the Nihilanth's head, rendering it impervious to damage. These are consumed as the Nihilanth takes damage, but specialized crystals within the upper portion of its chamber replenish the spheres as they vanish. After Gordon destroyed these crystals, the shield put up by the orbs will not regenerate anymore. After a massive amount of damage is done, the shield drops and the orbs disappear, leaving his body exposed and susceptible to damage. At this point, the glow of his brain is visible through his head.

After a large amount of damage is done to the Nihilanth's body (more than it takes to blow up an M1A1 Abrams) the Nihilanth's head opens up like a flower, revealing a shining, vulnerable brain. After a significant amount of damage is done to this, the Nihilanth floats up to the roof of its chamber and dies in a massive green explosion