Silas discovered what Qetsiyah had "done" and was completely devastated, changing the life and the fate of the young witch forever. Qetsiyah gave Silas an ultimatum after Silas had found out that Amara had "died": to surrender to her, give up his immortality and take the cure so that he would become a mortal witch again, with the intention that he spend the rest of his mortal life with Qetsiyah instead. Silas refused to adhere to Qetsiyah's wishes, so she incapacitated him with the use of her magic.
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Qetsiyah was born sometime during 1st century B.C., in Ancient Greece. Qetsiyah was a beautiful young lady who was the most powerful witch in a group of very "gifted" people called the Travelers. Also, a part of the Travelers was a handsome and powerful young witch named Silas with whom she fell madly in love. The two eventually became engaged to be married, and when Silas told her he wanted to be with her forever, Qetsiyah created a spell that would make them both immortal. Qetsiyah successfully made an immortality elixir, which they would consume on their wedding night. Qetsiyah created a whole garden for their wedding and prepared for Silas to join her so that they could commence their eternity together. As she waited for him at the altar, however, everything around her started to die and Qetsiyah realized that Silas was drinking the elixir from another location.

Knowing that Silas was up to no good, she tracked Silas down to a tent in the woods, where she had discovered that Silas' betrayal was even worse than what she had believed. Not only had Silas given the immortality elixir to another woman, but that woman was her handmaiden, Amara. Enraged, Qetsiyah found a way to reverse the spell, creating a cure for immortality before going to get her revenge. She waited until Silas had left before confronting Amara. She desiccated Amara, then faked her death to make Silas believe she was dead. Silas attempt to attack her for killing his love, however, Qetsiyah used her magic to neutralize Silas, and entombed him in a cave on a remote island. She buried him with the cure and with a choice: take the cure, become mortal and die, or rot as an immortal being for eternity. Silas chose to rot as an immortal being in darkness for eternity just to spite Qetsiyah.

Still, after entombing Silas, Qetsiyah wasn't satisfied. She knew that should Silas die a mortal death after ingesting the cure, his spirit would be reunited with Amara in peace for eternity as he had always planned. Determined to not allow that to happen, she created a supernatural purgatory, which eventually came to be known as the "Other Side," where all supernatural creatures would go when they died. She bound the Other Side to Amara, as she needed something eternal and indestructible to bind it to so that it would never fall. This ensured that, if Silas was ever freed and succeeded in his plan to die, he would never be reunited with Amara, even if the Other Side did happen to fall because he would be unwilling to kill his beloved soulmate.

At some point, Qetsiyah was killed by the Travelers. From the Other Side, she was forced to watch as Silas refused to take the cure. To add insult to injury, when Silas and Amara became immortals, they violated the natural law that all things must die, so Nature found a balance by creating what they call "shadow-selves," or doppelgängers, who could die in their place. While on the Other Side, she was forced to watch Silas and Amara's shadow-selves find each other and fall in love for two thousand years, believing it to be the universe's way of demonstrating that their souls were forever bound. However, in reality, they were only drawn together because of a spell a Traveler named Markos cast in the 5th century.

Roughly a thousand years later, an altered version of Qetsiyah's immortality spell was used by the witch, Esther Mikaelson, to turn her husband and children into immortals, which involved the use of blood from one of the doppelgängers (a woman named Tatia) that came to exist as the result of Qetsiyah's original immortality elixir. However, though both species possessed an insatiable craving for human blood, the alterations Esther made to Qetsiyah's spell begat a supernatural being who possessed different abilities than those Silas and Amara gained upon their transformations, and they were not nearly as invulnerable to death as the true immortals. In time, this new species eventually became known as the first vampires.

A hundred years after the creation of vampires in 1001 AD, Qetsiyah's descendant, an elderly witch who was dying from ill health, created the Brotherhood of the Five hunters, with one mission: find Silas' tomb, force-feed him the cure, and kill him. However, the first five hunters were killed by Niklaus Mikaelson, one of the Original vampires whose werewolf heritage had been bound with a curse. Due to this circumstance, their mission found itself sidetracked, and the spell that bound the five hunters were forced to adapt to new hunters who neither had the benefit of the full map to the cure nor were they aware of the exact nature of their supernatural mission.