Roger Dearly (Jeff Daniels) is an American video game designer who shares his home in London with his pet dalmatian, Pongo. One day Roger takes Pongo for a walk, and the dog sets his eyes on a beautiful female Dalmatian named Perdy. After a frantic chase through the streets of London, Roger and Pongo discover that
Perdy likes Pongo; and Perdy's owner, fashion designer Anita Campbell-Green (Joely Richardson), is taken with Roger when they meet in St. James Park. Romance blossoms between both human and canine couples and Roger and Anita walk down the aisle.
Anita works as a fashion designer at the House of de Vil. Her boss, Cruella de Vil (Glenn Close), has two passions in life: cigarettes and fur. Anita, inspired by her dog designs a coat made with spotted fur. Cruella, leaps on the idea of making garments out of actual Dalmatians. When Cruella learns that Perdy has given birth to 15 Dalmatian puppies, she offers the couple a decent price for the newborn puppies, but the couple refuses. Flying into a maniacal rage, Cruella relieves Anita of duty and vows to get even. She has her henchmen, Jasper and Horace (Hugh Laurie and Mark Williams respectively), steal the puppies and deliver them to her ancient estate, De Vil Mansion.
With the help of the other dogs and animals scattered throughout London, the puppies manage to outwit Jasper and Horace, and escape to a farm, where their parents have been called to wait. But shortly after, Cruella shows up and tries to retrieve them; she ends up having a pig sit on her, after which she falls into a vat of molasses (caused by raccoons) and is kicked into a pig pen by a horse. All of the Dalmatians get home by the Metropolitan Police Service, who then arrest Cruella and her henchmen. The family adopts the other Dalmatians Cruella stole, bringing the total to 101. Roger designs a successful video game featuring dalmatian puppies as the protagonists and Cruella as the villain, and they move to the English countryside with their millions.