The enemies of the game, the Necromorphs, as a whole are disturbing looking monstrosities. They all originate from human corpses mutated by alien life, hideously deformed and reshaped to better suit the Necromorphs' needs. While all of them are indeed terrible abominations, their size and shape can vary greatly. Also, one peculiar characteristic of most Necromorphs is that they have an "enhanced" form, jet-black in color, which is usually twice as resilient as its ordinary brethren.
- Slasher: Slashers are the cannon fodder of the Necromorphs' "army", and the most obviously human of all. They stand upright on human legs, and their original human arms, which have been reduced to deformed, useless appendages, are located in a bloody hole in their bellies. From their shoulders protrude massive arms ending in scythe-like protrusions, hence their name, and attack by charging and viciously flailing their scythes. Their heads are small and encased between their arms, and their lower jaw is missing, replaced by small red tentacles.
- Lurker: Lurkers are the result of the Necromorph infestation on a human baby, and thus looks disturbingly like monstrously mutated infants. They are small and walk on all fours, but can walk on walls and ceilings. They attack with three tentacles that protrude from their backs. The tentacles can also fire noxious needles with great range and accuracy. The Lurkers are individually weak, but their small size and ability to climb on walls and ceilings, and their ranged attacks, can pose a problem.
- Infector: Infectors are the mutated bodies that help spread the Necromorph "infection". They look like a human torso with the legs snapped backwards and skin stretched over them to create a "wing" effect. These creatures can fly short distances but prefer to crawl along, stabbing deceased crew members with a long proboscis, causing them to turn into Necromorphs. They are more interested in the dead crew rather than Isaac and so they will only attack him if there are no bodies to infect.
- Brute: Brutes are very large, lumbering, quadrupedal monstrosities formed by fusing many corpses together. As their name implies, Brutes possess enormous strength and attack by flailing with their giant arms, or charging head-on. They also possess nearly invulnerable natural armor on their front, though their back is completely devoid of armor. They are vulnerable to attacks from behind, but given their speed and sheer power, getting into position for a clean shot is indeed difficult.
- Pregnant: Similar to the Slashers in that they walk on legs and have scythe-armed appendages, Pregnants are hideously obese and sickly green in color, with scything talons that are almost twice the size of a normal Slasher. They are usually slow and walk at a very lumbering pace, but when prompted to attack they can make frightening bursts of speed. While they are indeed perilous, the greater danger comes from their bellies: given its name, a Pregnant that is shot in its bloated body will spew several Swarms, adding to the number of enemies to defeat.
- Swarm: Swarms are the creatures that come from a Pregnant who has been shot in the belly, and sometimes are found in independent swarms or inside item crates. They are extremely weak, but tend to swarm en-masse and do a lot of damage to Isaac by attaching themselves to his body. However, their weakness and the density of their swarms can be cleverly used against them. They appear as a small lump of green flesh with small tentacles, and move by rolling with their appendages. They can leap great distances.
- Leaper: Leapers are scorpion-like Necromorphs, human corpses whose legs were merged together to form a long, muscular tail, and whose arms became crab-like. They are very fast and can leap great distances. They attack by flailing their long tails, or by biting viciously with their saber-toothed mouths. Leapers can be a problem when they ambush you in Zero-G locations, taking advantage of their ability to crawl on walls and ceilings combined with their leaping abilities.
- Exploder: These are the suicide bombers of the Necromorph species. These former humans are twisted and mangled into a body with both legs entwined, one long arm and one arm that has grown into a pustule of volatile chemicals. When an exploder gets close enough to Isaac it will strike its exploding arm against the floor. This causes great damage to Isaac, the exploder itself (which is killed in the blast), and any other Necromorphs within range. If the exploding sac is separated from the Necromorph, it will instead attack with its remaining arm. The exploder's face is slit down the middle, and as it walks its head flops open and shut.
- Divider: Disturbing-looking and extremely tall, Dividers have elongated limbs tipped with claw-like hands. They are very thin, slow (but capable of bursts of speed similar to other Necromorphs) and strong, and attack with tentacles from their bellies and striking with their hands. Also, as their name suggests, once defeated their head, torso, arms and legs become independent creatures, continuing to stalk and assault the player. As divided monsters they are fast and hard to hit, but much weaker.
- Twitcher: These Necromorphs were human soldiers whose bodies were infected and mutated into gray-skinned, bulky and more heavily armed versions of ordinary Slashers. While very strong, their most frightening virtue is their speed: as soldiers they all possessed Stasis Modules that were assimilated into their bodies during mutation. As a result, they are so fast that they're capable of dodging bullets in flight, and twitch uncontrollably as a side-effect. They are slightly less durable than normal Slashers, but are a far greater threat.
- Wheezer: These Necromorphs are almost completely human, except for their grey skin and bloated sacs on their back. Incapable of movement, they crouch on their legs while expelling extremely noxious gases from their sacs. They're harmless except for the contaminated air they expel, forcing Isaac to use his oxygen reserve when in their vicinity. Wheezers are different from other enemies in that they're only encountered in one chapter, and must be destroyed to purge the air.
- Tentacle: Usually found attached to larger Necromorphs, Isaac is also attacked by single tentacles. These tentacles appear from holes in walls, or from large crevasses on the ship. They attempt to drag Isaac back to their unknown source several times during the game. Some also attempt to simply crush Isaac. All tentacles have a glowing weak spot on their side that when breached, severs the tentacle in two and causes it to retreat.
- Guardian: Some of the strangest of all the Necromorphs, the Guardians are enormous lumps of flesh attached to walls, from which protrude a human torso with its intestines dangling under it. It wails and screams as little, tentacle-armed sacs comes out from its belly. Guardians cannot move, and while they can flail their viscera in a whip-like fashion, the little creatures they spawn are their primary offensive capability. If Isaac gets too close, their squid-like tentacles can decapitate him, killing him instantly. Usually, as its name implies, a Guardian (sometimes two) is found near a door through which you must travel.
- Hunter: The Hunter is a hulking, more imposing version of a Slasher, armed with enormous scythe-like appendages. It can regenerate lost limbs or heal wounds at incredible speed. One of these beasts is unleashed to hunt down and kill Isaac, who is incapable of killing it by normal means (at best you can temporarily disable the creature).
- The Leviathan: This is the first major Necromorph of the game. It is encountered on the Hydroponics deck, having made its nest in the enormous, cylindrical, zero gravity Food Storage room. As its name suggests, the Leviathan is an enormous, writhing mass of flesh and muscles with a central mouth and three long, thick tentacles. It attacks by flailing its appendages and spitting organic spheres from its mouth, which explode on contact.
- The Slug: A titanic blob of flesh, this monstrosity rests on top of the Ishimura, tightly attached to the ship's hull. If defeated, it will detach itself from the ship and float away into space.
- The Hive Mind: The source of the Necromorphs and their ultimate being. It is found on Aegis 7, where it nests inside a massive crater. The beast itself is nightmarish: it is a gigantic, segmented, worm-like monster, with tentacles growing nearly everywhere on its skin, comparable to a bole with limbs on its sides. Its sheer size dwarfs the player; Isaac himself is smaller than the creature's orifice. The Hive mind can create Pregnants from its mouth, and uses its larger tentacles to crush its prey. The hive mind has a cluster of strange organs around its mouth and behind its "ribs".