Werewolves (also called Lycanthropes, Loup Garou, and Beasts) are a near-extinct supernatural species of individuals who unwillingly transform into fearsome and extremely hostile wolves on the night of the full moon. Even in their human form, werewolves possess superhuman physical prowess, but not to the same level as a vampire and not as powerful as the abilities they have on a full moon. These creatures are the most dangerous enemies of vampires, due to their bite, which is lethal to them. Werewolves are also hardwired to kill vampires on sight in their wolf form, though they still hunt human prey whenever there are no vampires to kill.
A werewolf has to kill a human in order to trigger their werewolf gene. It does not matter if the kill was accidental or intentional, the werewolf gene will still be activated. After the gene is triggered, the werewolf's eyes will turn yellow and their powers will activate instantly. A werewolf who has yet to trigger his or her curse will only exhibit increased aggression and overwhelming fits of rage during nights of the full moon. Also, until then, they are considered to not be supernatural, as Damon was able to compel Tyler just like any other human before Tyler triggered his werewolf gene
- Broken Neck - Breaking a werewolf's neck will results in instant death.
- Wolfsbane - When ingested, wolfsbane causes a werewolf to become severely weak and feverish. Also, If a werewolf's skin is exposed to wolfsbane, it will burn them.
- Magic - Witches are able to curse and inflict any supernaturals with enhanced healing abilities with aneurysms that cause the blood vessels in their brains to explode and heal over and over again.
- Heart Extraction - Ripping a werewolf's heart out will result in instant death.
- Blood Loss - If a werewolf is severely wounded and bleeds out before they can heal, they can die. As when Stefan threw a stake into one's jugular, the werewolf bled out and died before it could fully heal, as well as when Klaus impaled the werewolf Paige through the chest.
- Decapitation - Decapitation will result in instant death for a werewolf.
- Presumably Fire - Fire can presumably kill a werewolf. It can also hurt them.
The Devil's Star - The Devi's Star can cause one thousand cuts onto another's body, regardless of species. As they are mortal, it will most likely kill them.
- Suffocation - Unlike Vampires,which after their lungs collapse as they are already dead are reanimated, a werewolf will die from lack of oxygen, meaning they can die by drowning or being smothered.
- Physical Trauma - Minor physical injuries such as gunshots, stab wounds and broken bones will cause a werewolf pain and will also slow them down. However, this is only temporary, as they will heal completely within minutes.
- Power Suppression Necklace - As seen in Every Mother's Son, Esther made a necklace to suppress Klaus's anger and powers as an untriggered werewolf, rendering him weak, but in control of his emotions. It is unknown if these types of jewelry would work on a triggered werewolf or a hybrid.