Cruella appears in the fourth and fifth seasons of the TV series Once Upon a Time, where she is portrayed as an adult by Victoria Smurfit, and as a child by Milli Wilkinson, as a witch who possesses the power to control animals.
A childhood sociopath, Cruella poisoned her father and two stepfathers. Her mother Madeline (Anna Galvin) kept her locked inside the house to prevent her from harming others. As an adult, she met Isaac (the Author) (Patrick Fischler), who was posing as a regular journalist; through him, she learned that her world, a perpetual 1920s England, was one of many. Smitten with her, the Author gave her the power to control animals. Cruella used the new power to have her mother's dalmatians kill her, and killed them and made their fur into a coat. In a struggle to prevent the Author from writing another note about her, the vial of magic ink spills on her causing her blonde hair to turn into the iconic black and white. However, the pen had a remnant of ink in it, which the Author used to write down a note that would, from there on, prevent Cruella from taking another life. "Cruella De Vil can no longer take away the life of another." Cruella kept this secret, as intimidation would still work for her needs.
She later ended up in the Enchanted Forest, where she became infamous for turning animals into outerwear. Rumplestiltskin (Robert Carlyle) recruited her, Ursula (Merrin Dungey) and Maleficent (Kristin Bauer van Straten) to acquire the Dark Curse. However, he double-crossed them and left them to be killed by the Chernabog. Escaping together, Cruella joined the two in trying to get assistance from Snow White (Ginnifer Goodwin) and Prince Charming (Josh Dallas) in preventing the Evil Queen (Lana Parrilla) from casting the curse. However, the Tree of Wisdom they consulted refused to answer due to Snow's pregnancy. Along with Ursula, Cruella was asked by Maleficent to act as a guard while she went through childbirth as a dragon. As a result, Cruella was sucked into a portal with Ursula and the child to the Land Without Magic, due to a spell cast by the Apprentice. She and the Sea Witch steal the egg the baby was in and use the magic to prolong their youth in the magicless world. She later marries a Mr. Feinberg and lives in a mansion off Long island in New York.
In the present day, Cruella's marriage has fallen apart as the FBI is repossessing her husband's belongings. Mr. Gold and Ursula convince her to join them in finding the Author to get happy endings. Cruella plays little importance in the plot, until the Author is released from the book; unable to kill him herself, she pretends to threaten Henry Mills's (Jared S. Gilmore) life to force Emma (Jennifer Morrison) and Regina to do so. However, Emma confronts her, not knowing the restriction the Author placed on Cruella, and magically blasts her off a cliff to her death.
After her death, Cruella ends up in the Underworld, a purgatory run by the deity Hades. While there, she meets David's twin brother James; they quickly strike up a romantic relationship due to their similar personalities. When the heroes arrived with Gold to rescue the recently deceased Killian Jones (Colin O'Donoghue), Cruella is among the deceased of whom they come across. In hopes of returning to life, Cruella appeals to Henry, the new Author, to use the quill to bring her back to life. Later, she helps Regina Mills locate the grave of her lost love Daniel, who has since moved on to a better place. Mistaking David for James, Cruella makes a move on him, then informs him of the hostility James holds toward his brother. Cruella and James then hatch a plan to get out the Underworld by delivering Hades the child of Robin and Zelena. James pretends to be David and puts a magic blocking bracelet on Emma, while he and Cruella take the baby. They take Emma and Robin to the docks, planning to throw them into the River of Lost Souls, until David and Hook stop them. David ends up throwing James into the River and Cruella runs off.
Once Hades' heart is restarted, and he plans to leave the Underworld with Zelena, Cruella teams up with the Blind Witch; Hades offered to let them rule the Underworld in his absence and help trap the heroes there. Delighted with the idea of getting to torment souls for eternity, Cruella agrees to the deal.
Following the heroes' escape back to Storybrooke, Hook teams up with a deceased King Arthur to locate the storybook so they can tell Emma how to defeat Hades. They go to find Cruella at the diner, where she reacts with disdain towards seeing Hook, but she coyly regards Arthur with keen interest because of his good looks. When questioned about the haunting booth, Cruella admits she destroyed it for good, since she doesn't want anyone moving on if it means she has to be stuck in the Underworld too. Hook then presses her about the book's whereabouts, which Cruella is surprisingly forthcoming about. She knows they will eventually figure out the truth even if she lies, and then tells them that she put the book in the River of Souls. Cruella is later dethroned by Arthur who then rules the Underworld for fifty years as she becomes a depressed and bored woman who drinks in the local bar with Sir Mordred.