The game features numerous enemies, all of which are supernatural in origins.
- Gargoyle - A small, red flying creature with only a claw attack. This is the first creature encountered in the game.
- Fire Gargoyle - Indistinguishable from a gargoyle until they attack, these can throw small fireballs.
- Golem - These humanoid rock creatures have only a melee punch attack. They will sometimes drop wand crystals upon death.
- Nitro Golem - Resembling normal golems, they can erupt in flame and fire homing skulls at the player. Like normal golems, they will sometimes drop wand crystals upon death.
- Undead Warrior - Skeletons clad in armor, they throw green ethereal axes at the player. Occasionally, they will throw a red, more damaging axe instead. They sometimes drop ethereal arrows.
- Disciple of D'Sparil - These appear to be shrouded humanoids, though underneath their black robes is only shadow. They can fly and attack with a spell that shoots purple rings in a spread of three. They will occasionally drop claw orbs, and rarely drop Tomes of Power. Their arcane chants are actually reversed messages. Its sighting sound says, "Destroy the Heretic!" and its active sound says, "Succumb to us, Heretic!"
- Sabreclaw - These vaguely humanoid armored figures have scorpion tails and iron claws. While they don't have a ranged attack, their melee attacks are rather formidable. They occasionally drop lesser runes.
- Weredragon - These large beasts have draconic features and shoot large fireballs. When they die, they sometimes drop ethereal arrows.
- Ophidian - Appearing starting in the third episode, these creatures have the lower body of a rattlesnake while the head is humanoid with serpentine features. They wield tridents from which they fire shots of magic in bursts. They will occasionally drop flame orbs.
- Iron Lich - First appearing as the boss of the first episode, these rather deadly creatures are found in many levels in later episodes. They appear as large metal skulls with glowing eyes and massive grins. They have three attacks. One of them is a whirlwind, which chases and tosses you into the air. Another is a pillar of fire that toasts anything in its path. The third is a spiked ice ball that splits into eight fragments upon impact that travel in the eight standard directions. Occasionally, they will drop a claw orb or Morph Ovum.
- Maulotaur - Appearing first as the boss of the second episode, these minotaur-like creatures can shoot volleys of fireballs and can charge you,. They can also pound the ground and send searing, explosive fire through the earth toward you. This fire travels along the ground, over ledges and down cliffs, and explodes very powerfully. They can drop flame orbs which give the player as many phoenix rod shots as inferno orbs. They can also drop mystic urns on occasion.
- D'Sparil - This is the final villain the player encounters, one of the Serpent Riders. He initially appears riding a chaos serpent, wearing red and gold robes. When you deal him enough damage, his mount dies and he becomes even more formidable. He can summon disciples, teleport, and hurl electrical charges at the player. He appears only in the final level of the third episode. It is interesting to note that his chanting, when played backwards, says, "surrender to D'Sparil".
Golems and undead warriors, sometimes appear as translucent ghosts that can only be hit with magical weapons such as the gauntlets, elven wand, ethereal crossbow (center bolt), dragon claw, phoenix flames, or hellstaff. Man-made weapons, such as the staff, the side arrows of the crossbow, the phoenix projectile, or the mace balls, simply pass through. A few of the enemies reappear in Hexen: chaos serpents are separate and fairly common creatures with much fewer hitpoints, maulotaurs can be summoned by the player to attack enemies, and the dark bishops and the Heresiarch appear similar to the disciples. The Heresiarch looks much like the sorcerer displayed in Heretic's final cutscene.