After three years in prison, Cruella De Vil is cured from her lust for fur coats. Dr. Pavlov proceeded this through an experiment that turns a predator and a prey into best friends. Cruella is released on a parole that states she has to pay eight million pounds to all dogs' homes of Westminster if she vows to never go back to dognapping. She changes her name from Cruella to "Ella", and locking away her old fur coats and a drawing of her in a Dalmatian puppy coat. She later meets up with Chloe Simon. "Ella" doesn't stay cured for long, however, as she turns back into Cruella the moment she hears the chimes of Big Ben. Just discovering this himself, Dr. Pavlov decides to never tell anyone about the liability. When Cruella sees Chloe's dogs, Dipstick and his puppies, she plans to make an ultimate fur coat with a hood.
Her servant Alonzo is sent to find a few puppies and she hires Jean-Pierre LePelt to help her in the capture of 102 puppies. They set Kevin Shepherd up, the owner of the animal shelter where Cruella spent community service. His animal shelter was the only one in the borough that allowed Cruella to trick the authorities in thinking that Kevin kidnapped the puppies to frame her and collect money. Kevin escapes from prison, however, with the help of Waddlesworth and he meets up with Chloe. They learn that Cruella is headed to Paris and they decide to follow her. However, they are soon captured by Cruella and imprisoned in her fur coat factory.
Oddball, being born without any spots, Cruella forgets about her and the puppy is able to rescue her family and the other dognapped puppies. Alonzo decides that he doesn't want to work with Cruella anymore and stand up to Lepelt and defeats him when he falls through the floor. He becomes a good guy and also helps Chloe and Kevin escape. The puppies are escorted to an abandoned baking factory, Cruella gives chase but accidentally activated the old bakery's machinery while dangling from the master control board wire. She falls down onto the processing line and puppies use the machinery to scare her. Cruella gets beaten and tormented by the machinery used by the puppies, a massive rolling pin, an array of slicers, a vat of cake mix, and a large oven. Oddball turns Cruella into a cake. Cruella and LePelt are arrested by French police, and Oddball saves the day. The real happy ending is when the dog shelter gets Cruella's money and when Oddball gets her first spots, letting everyone celebrate.
- Cruella De Vil: Glenn Close
- Kevin Shepherd: Ioan Gruffudd
- Chloe Simon: Alice Evans
- Alonzo: Tim McInnerny
- Dr. Pavlov: David Horovitch
- Mr. Torte: Ian Richardson
- Jean-Pierre Le Pelt: Gérard Depardieu
- Waddlesworth (voice): Eric Idle
- Agnes: Carol MacReady
- Ewan: Ben Crompton
- Le Pelt's Assistant: Kerry Shale
- When the Orient Express is leaving, it is pulled by the famous LNER Class A3 4472 (a.k.a. The Flying Scotsman), then when in France, it is pulled by the BR Standard Class 5 73082 (a.k.a. The Camelot).
- It is odd how none of the baggage helpers checked what was inside Dipstick, Dottie, Domino and Little Dipper's box. Also, it is odd how nobody recognized Cruella.
- Originally, the film was supposed to be called 101 Dalmatians Return.
- Since Dalmatian puppies grow so fast, each pup only got to "act" for two weeks before being replaced by a younger pup.
- The film featured 55 "spot removal artists." In order to make the Dalmatian "Oddball" completely without spots, the production team tried putting make-up on the dogs, painting off the spots, putting plain white suits on the dogs, and finding another breed of dog. However, none of these techniques worked, so the spots eventually had to be digitally removed (erased in each shot).
- The "Oddball" that rolls around on the copy machine was adopted by one of the trainers and named "Lala."
- When Chole and Kevin go out on their date, the Dalmatians can be seen watching Lady and the Tramp on TV.
- As in 101 Dalmatians, when Cruella is foiled by the Dalmatian puppies, she is wearing a red and black fur coat.
- This film was where Alice Evans and Ioan Gruffudd first met and fell in love during production, later married on September 14, 2007.
- Walt Disney Pictures completely produced this sequel on its own, while the first movie was produced by Great Oaks, which was dissolved after the release of Flubber.