Pongo and Missis Pongo are a pair of Dalmatians who live with the newly married Mr. and Mrs. Dearly and their two nannies. Mr. Dearly is a "financial wizard" who has been granted life-long tax exemption and lent a house on the Outer Circle in Regent's Park in return for wiping out the government debt. The dogs consider the humans their pets, but allow the humans to think that they are the owners.

Missis gives birth to a litter of 15 puppies. Concerned that Missis will not be able to feed them all, Mrs. Dearly looks for a wet nurse, and finds an abandoned Dalmatian mother in the middle of the road in the pouring rain. She has the dog treated by a vet and names her Perdita.

Mr. and Mrs. Dearly attend a dinner party hosted by Cruella de Vil, an intimidating and very wealthy woman fixated with fur. The Dearlys are disconcerted by her belief that all animals are worthless and should be drowned. Shortly after the dinner party, the puppies disappear. The humans fail to trace them, but through the "Twilight Barking", a forum of communication in which dogs can relay messages to each other across the country, the dogs manage to track them down to "Hell Hall", the ancestral home of the de Vil family in Suffolk.

Pongo and Missis decide to run away from home and find them, leaving Perdita to look after the Dearlys. After a journey across the countryside, they learn that there are 97 puppies in Hell Hall, including their own 15.

Thus commences a determined attempt to rescue the Dalmatian puppies quickly before they end up as fur for one of Cruella de Vil’s famous black and white fur coats.