Resume : Songwriter Roger Radcliffe lives in a bachelor flat in London, England along with his dalmatian Pongo. Bored with bachelor life, Pongo decides to find a wife for Roger and a mate for himself. While watching various female dog-human pairs out the window, he spots the perfect couple, a woman named Anita and her female dalmatian, Perdita. He quickly gets Roger out of the house and drags him through the park to arrange a meeting. Pongo accidentally causes both Roger and Anita to fall into a pond, but it works out well as the couple falls in love. Both couples marry.

Later, Perdita gives birth to 15 puppies. One almost dies, but Roger is able to revive it by rubbing it in a towel. That same night, they are visited by Cruella De Vil, a wealthy and materialistic former schoolmate of Anita's. She offers to buy the entire litter for a large sum, but Roger says they are not for sale. Weeks later, she hires Jasper and Horace Badun to steal them. When Scotland Yard is unable to determine the thieves or find the puppies, Pongo and Perdita use the "Twilight bark", normally a canine gossip line, to ask for help from the other dogs in London.

Colonel, an old sheepdog, along with his compatriots Captain, a gray horse, and Sergeant Tibbs, a tabby cat, find the puppies in a place called Hell Hall (Cruella's abandoned and dilapidated family estate, also known as The De Vil Place), along with many other dalmatian puppies that Cruella had purchased from various dog stores. Tibbs learns they are going to be made into dog-skin fur coats and Colonel quickly sends word back to London. Upon receiving the message, Pongo and Perdita immediately leave town to retrieve their puppies. Meanwhile, Tibbs overhears Cruella ordering the Baduns to kill and render the puppies that night out of fear the police will soon find them. In response, Tibbs attempts to rescue them himself while the Baduns are preoccupied watching television, but they finish their show and come for them before he can get them out of the house. Pongo and Perdita break into the house through a window and confront the Baduns just as they have cornered and are about to kill them. While the adult dogs attack the two men, Colonel and Tibbs guide the puppies from the house.

After a happy reunion with their own puppies, Pongo and Perdita realize there are dozens of others with them, 99 altogether including the original 15. Shocked at Cruella's plans, they decide to adopt all of them, certain that Roger and Anita would never reject them. They begin making their way back to London, aided by other animals along the way, with Cruella and the Baduns giving chase. In one town, known as Dinsford, they cover themselves with soot so they appear to be labrador retrievers, then pile inside a moving van bound for London. As it is leaving, melting snow clears off the soot and Cruella sees them. In a maniacal rage, she follows the van in her car and rams it, but the Baduns, who try to cut it off from above, end up colliding with her. Both vehicles crash into a deep ravine. Cruella yells in frustration as the van drives away.

Back in London, Roger and Anita are attempting to celebrate Christmas and his first big hit, a song about Cruella, but they miss their canine friends. Suddenly, barking is heard outside and, after their nanny opens the door, the house is filled with dogs. After wiping away more of the soot, the couple is delighted to realize their companions have returned home. After counting 84 extra puppies, they decide to use the money from the song to buy a large house in the country so they can keep all 101 dalmatians.