- "What sorcery is this?"
- ―Darth Tyranus
During the Clone Wars, the Nightsisters undertook a mission to assassinate Count Dooku after he betrayed his apprentice Asajj Ventress. Taking Karis and Naa'leth to Dooku's palace on Serenno, Ventress sought revenge, but the Sith Lord repelled the attack, defeating his assailants.
During the Battle of Sullust, Darth Sidious contacted Dooku, telling Dooku that he was becoming concerned about the power of their enforcer, Ventress. Dooku, not wanting to admit he had been training her to help overthrow his master, ordered their forces to abandon Ventress to her death. She was recovered in her damaged Ginivex-class fanblade starfighter by a salvage crew, and commandeering their ship, she returned to her homeworld Dathomir. There, Mother Talzin agreed to aid in getting revenge on Dooku, providing poisons and invisibility potions.
- "I will not need my eyes to see you, Jedi!"
- ―Dooku, mistaking the assailants to be Jedi before attacking them
Asajj Ventress and her two Nightsisters became invisible and infiltrated Dooku's palace. Ventress shot a poison dart into Tyranus's neck that blinded him, although he could still sense them through the Force and mistook them as Jedi. Ventress attacked Dooku with a lightsaber, beginning their duel in the Count's bedroom and eventually leading into his office. Ventress, who had managed to stay disguised during the entire confrontation, managed to disarm the Sith Lord and was about to strike the killing blow, but Tyranus defended himself by striking Ventress and her accomplices with Force lightning, throwing them out the window and over a cliff, ending the attack. However, the three Nightsisters survived and returned to Dathomir.
- "Where one sees failure, others see opportunity."
- ―Mother Talzin
Due to his attackers' use of Jedi lightsabers, Tyranus mistakenly believed that the Jedi had tried to assassinate him. Wishing to protect himself, he sought a new apprentice to replace Ventress (whom he erroneously believed to be dead).
Given the failure of their direct attempt to kill Tyranus, the Nightsisters developed a new plot to kill the Sith Lord using a double agent. To arrange the plan, Mother Talzin contacted Tyranus, offering to provide one of the Nightbrothers to be his new assassin. Tyranus, seeing this as an opportunity to get the new apprentice he desired, agreed. After selecting Savage Opress to be their pawn, Talzin presented the hulking Zabrak to Tyranus, who was pleased with his new warrior, unaware of his true loyalties.
- Star Wars: The Clone Wars – "Nightsisters" (First appearance)
- Star Wars: The Clone Wars – "Monster" (Appears in flashback(s))
- Dark Disciple (Mentioned only)