A while after Roger and Anita have married and settled down together, Perdita, Anita's dalmatian, hears the screech of Cruella's car outside, and runs to the kitchen to hide from 'that devil woman'. Looking out of the window, Roger sees that Cruella, whom he refers to as Anita's old schoolmate, is coming towards the house. As she approaches the front door, Roger sings less-than-flattering song about Cruella; Anita attempts to stop Roger for fear that Cruella might hear. Roger goes upstairs and uses various musical instruments to play the tune to the song when Cruella bursts in, demanding to see Pongo and Perdita's puppies, and leaving a trail of smoke from her cigarette. Anita informs her that the dalmatian puppies will not arrive for a few weeks. After commenting on Pongo and Perdita's 'beautiful coats', Cruella leaves, saying that she will return in 3 weeks. A previously excited Perdita grows anxious at Cruella's interest in the puppies.

Cruella returns to the Radcliffe's house just after the fifteen puppies are born. At first she is furious that the 'mongrels' have no spots, but, when Anita tells her that the spots will appear in a few weeks, Cruella offers to buy all fifteen immediately. Roger refuses any price, and Cruella, after realizing he is not joking, storms out, vowing revenge. Later, Horace and Jasper Badun succeed in stealing the puppies while the Radcliffe's are out. At home, Cruella laughs to herself as she reads of the theft in the newspaper; she is the orchestrator of the crime. The Baduns phone her to demand payment, but are told that they will receive nothing until the job is done. Slamming the phone down, Cruella then decides to phone Anita, and feigns surprise at the theft (though Roger is convinced that she is involved).

The Baduns succeed in stealing another eighty-four puppies, and take them to the Old De Vil Place. Cruella arrives one evening, demanding that 'the job' be done immediately, and leaves furiously, threatening to call the police otherwise. Sergeant Tibbs succeeds in helping all ninety nine dalmatians escape the old mansion. Cruella and the Baduns search for the puppies in a small village, and Cruella is initially fooled when the dogs cover themselves in soot to disguise as labradors and board a lorry heading for London (Horace although was convinced about the Puppies disguising themselves with soot, but Jasper said sarcastically that they were and then angrily yelled "You Idiot!!"). When she sees snowflakes removing the soot, however, she follows in her car, and the Baduns follow in their truck. Pursuing the puppies, Cruella almost succeeds in ramming the lorry, driver, dalmatians and all, off a cliff, but the top of her car is ripped off during the chase, which comes to an end when the Baduns, trying to hit the lorry, succeed in ramming their truck into her car, sending Cruella, Horace, and Jasper over the cliff; all 3 survive, but Cruella is furious and subjects Jasper and Horace to a tongue-lashing at which point Jasper finally plucks up the courage to tell her to shut up. Consumed by anger and humiliation, Cruella collapses into manic sobs and was arrested after the police recognizing her as the thief.

For the live-action version of 101 Dalmatians, Cruella was reinvented as the head of a London-based fashion house, House of De Vil. Rather than an old schoolmate, Anita Dearly is one of her employees and, it is implied, her best designer. Cruella first takes a fancy to Dalmatian skin when Anita draws spots on one of her dress designs. Along with Jasper and Horace, Cruella had a new accomplice: Mr. Skinner, who is given the job of killing and skinning the puppies. As the head of a fashion house, Close's Cruella was given a more varied wardrobe of furs, including an enormous, red cloak, a Siberian tiger pelt, and clawed gloves. This version of the character was less invincible than her animated predicessor, and it is the animals of a nearby farm who defeat her, in slapstick fashion, to leave her muddy, covered in manure but uninjured, after which she is arrested.

A live-action incarnation was portrayed by Glenn Close for a remake, 101 Dalmatians; this version was not only an heiress but also a fashion designer, and was defeated in slapstick fashion similar to the defeats of the villains of the Home Alone movies (which were produced by the same producer). Glenn Close became famous for her role.