Appearing only in zero gravity environments, Medusas are best to be avoided. If you get close, they can deliver a devastating melee attack with one of their four limbs. They can also fire projectiles that home in on targets. Therefore, it is better to engage them at long range and kill them before they can attack. Aim at the large yellowish sacs or cut off their tentacles to kill them.
- Most of the time, it is wiser to conserve ammunition and simply manuever around them.
- Shoot the yellow sacs on their limbs (destroying the main sac will launch two or more projectiles).
The Medusa does not have a specific death scene of its own, instead Isaac or Carver will be split into pieces if the creature kills them with its limb-tentacle.
If Isaac/Carver was hit by a Medusa's homing projectile, whatever part of their bodies hit will be torn off.
- Like the Alien Necromorph, the Snow Beast, and the Nexus, the Medusa also seems to be a Necromorph based on a native lifeform from Tau Volantis.
- If a Medusa finishes off Isaac/Carver with its limb during a Zero-G flight, their bodies will be torn apart while their legs continue to drift off-screen with boosters still active.
- The Medusa is similar to the Nest, except it is a mobile form and much more advanced.
- In Greek mythology, Medusa was one of the three Gorgons and was said to be so ugly she could turn anyone she looked at into stone. This name is fitting, given the Medusa's grotesque appearance
- A Medusa is also the name given to the free-swimming stage of Cnidarians such as jellyfish, normally the reproductive stage of a sessile polyp. The Nest's physical appearance seems to support this, as they resemble the stationary polyps.