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American video game designer Roger Dearly lives with his pet Dalmatian Pongo in London. One day, Pongo sets his eyes on Perdita, another Dalmatian. After a chase that ends in St James's Park, Roger discovers that Pongo likes Perdita. Her owner, Anita Campbell-Green falls in love with Roger when they meet. When they return to Roger's home, Anita accepts his proposal. They get married along with Perdita and Pongo. Anita works as a fashion designer at the House of de Vil. Her boss, Cruella de Vil, has a deep passion for fur, going so far as to have a taxidermist, Mr. Skinner, skin a white tiger named Sue-Ling at the London Zoo to make her into a rug for her. Anita, inspired by her Dalmatian, designs a coat made with spotted fur. Cruella is intrigued by the idea of making garments out of actual Dalmatians, and finds it amusing that it would seem as if she was wearing Anita's dog.

Perdita gets pregnant, and so does Anita. Cruella visits their home and gets excited when she finds out Perdita is expecting too. Weeks later, she returns when a litter of 15 puppies are born and offers Roger and Anita £7,500 for them, but they refuse. Enraged, Cruella dismisses Anita and vows revenge against her and Roger. One winter evening, she has her henchmen, Jasper and Horace, break into their home and steal the puppies, while the couple is walking in the park with Pongo and Perdita. Along with 84 other Dalmatians that were previously stolen, they deliver them to her country estate, De Vil Mansion. Cruella asks Skinner to kill and skin them to create her coat.

With the family devastated at the loss of their puppies, Pongo uses the twilight bark to carry the message via the dogs and other animals of Great Britain, while Roger and Anita notify the police. Anita realizes Cruella was behind the kidnappings and confirms her suspicion when she shows Roger and Nanny her portfolio. An Airedale Terrier follows Jasper and Horace to the mansion, and finds all of the puppies, who he helps escape under the duo's noses. They make their way to a nearby farm, where they are later joined by Pongo and Perdita. Cruella arrives at the mansion and discovers what has happened. Angry with the thieves' failure, she decides to carry out the job herself. After several mishaps, Jasper and Horace discover nearby police looking for Cruella and hand themselves in, joining Skinner who was attacked in defence while trying to kill a puppy who have been left behind.