As Cruella de Vil (Glenn Close) emerges from a three-year prison sentence, she undergoes a profound transformation guided by psychologist Dr. Pavlov. With her obsession for fur coats firmly behind her, Cruella is granted probation with the strict warning that any violations will lead to her swift return to prison, as well as the loss of her eight million pound fortune which is destined for Westminster's dog shelters. To maintain her freedom, she must reconcile her turbulent relationship with her beleaguered valet, Alonzo, and acquire the Second Chance Dog Shelter from the beleaguered Kevin Shepherd (Gérard Depardieu), effectively saving it from financial ruin.
Meanwhile, her probation officer, Chloe Simon, remains skeptical about Cruella's newfound kindness, harboring suspicions about Dipstick, one of the original 101 Dalmatians, and his owner. As the story unfolds, Dipstick’s mate, Dottie, gives birth to three charming puppies: Domino, Little Dipper, and Oddball, the latter raising eyebrows with her unusual albino appearance. In another twist, Dr. Pavlov makes a notable discovery; exposing his therapy patients to sudden loud noises causes a reversion to their former selves, a detail he opts to keep secret for now.
As Big Ben chimes ominously, a transformation occurs, letting Cruella revert to her villainous self. With a surge of determination, she seeks out the mastery of French furrier Jean-Pierre LePelt to create a wicked new fur coat, intending to incorporate the innocent puppies as a hooded feature. Complications arise when Chloe and Kevin embark on a romantic evening, during which Kevin reveals the peril of Cruella breaching her parole, since any violations would result in the forfeiture of his entire fortune due to the state of his dog shelter.
Armed with this impactful information, Cruella begins to devise an elaborate scheme to frame Kevin for stealing the first 99 Dalmatian puppies taken by LePelt, leveraging his history of rescuing animals against him. As time runs out, she hosts a dinner party at her estate, slyly diverting attention while LePelt absconds with Dottie and her three puppies. However, after a series of unfortunate events, Dipstick is snatched away, leading a frantic Chloe to rush home. Tragically, she arrives too late, only to find hope ignited when Kevin manages to escape from prison thanks to his clever parrot sidekick, Waddlesworth. His past, it turns out, was not a conviction, but rather liberation of animals from a cruel lab.
With the fate of the Dalmatians hanging by a thread, the impending showdown between good and evil looms large. Can Chloe and Kevin outmaneuver Cruella’s sinister game? As destiny would have it, they discover LePelt's discarded ticket for the Venice-Simplon Orient Express, only to realize in despair that Cruella and LePelt are already en route to Paris. Undeterred, the duo attempts to catch up with them but falls short, while Oddball, escaping the chaos, takes it upon herself to stealthily follow Cruella and LePelt to LePelt's factory.
Upon arriving at the factory, Kevin and Chloe unwittingly become trapped by the cunning Cruella, who imprisons them in a dank cellar. Yet, they ingeniously manage to free the puppies through a hole in the ceiling, setting off a chain reaction that leads to Cruella’s eventual downfall. Pursuing the puppies on her own, Cruella finds herself in a bustling bakery, where the very puppies she sought to capture outsmart her, leading to a dramatic twist where she nearly gets baked alive in a massive cake. Miraculously, she survives this harrowing event, yet both she and LePelt are ultimately captured by the authorities.
With their names cleared of any theft, Kevin and Chloe return to London, where they are graciously presented with remnants of Cruella's wealth by Alonzo himself. In a final heartwarming chapter, Oddball, emblematic of the indomitable spirit and bond of the pack, finally grows a few spots, leaving all who witness this moment filled with wonder and joy.
