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- Susan Blakeslee as Cruella de Vil (credited as Susanne Blakeslee)
- Molly Marlette as Oddball
- Frankie Muniz as Domino
- Barbara Dirikson as Dottie
- Jeff Bennett as Dipstick, Jasper and Shellby
- Maurice LaMarche as Horace
- Jess Harnell as LePelt
- Eric Idle as Waddlesworth
- Nancy Cartwright as Fidget
- Eddie Izzard as Sgt. Tibs
- Tress MacNeille as Ivana
- Rob Paulsen as Fluffy
- Drew Varley as Chester
- John Partridge as Manny
- Kath Soucie as Priscilla
- Sherry Lynn as Crystal
The game itself follows the films' storyline loosely. The player can choose the role of one of two dalmatians, Oddball or Domino, who are out in the backyard looking for treasure. It is not long before the player realizes that a toy found buried in a park was made at one of Cruella de Vil's toy factories; this alludes to the fact that Cruella's toy sales are down, which ultimately leads to the problem in the storyline. Facing financial ruin from lack of sales, Cruella sets an evil plan in motion - to reprogram her toys to capture any pets in sight. Oddball and Domino are the only puppies in their family who have not been captured when they return from the park. Their parents, Dottie and Dipstick, set out to rescue their puppies, commanding Oddball and Domino to stay home and 'be good.' The puppies do not listen, and are soon out on their biggest adventure yet - to save their brothers and sisters, and their parents who are captured along the way.
Throughout the game, the puppies have to rescue their siblings, fend off Cruella's henchmen, and Cruella herself several times, while navigating through all kinds of terrain, leading up to a final battle at Cruella's toy factory, during which Cruella (and her "Dot Com Darling," Dr. Farzboom) are encased in Farzboom's own creation, "supergloop." Ironic, considering Cruella's plan was to encase all the puppies in this heavy-duty glue-like substance to create a line of realistic animal toys. The henchmen end up deserted on an island, and Cruella ends up in a jail cell, still glued to Farzboom.
Over the course of the game, the player has several opportunities to collect 'stickers' towards a virtual sticker book which can be accessed through the level menu. Various actions within the game will unlock stickers. Generally, there is a sticker for finding the first checkpoint and exiting every level, collecting 100 bones each level, and rescuing all the puppies in each level. Each level has its own individual tasks—completing a chore, defeating a henchmen, solving a puzzle, etc. -- which will also grant stickers. There are six stickers per a level, excluding Cruella levels, which combine together with mini games for their own sticker image.
Puppies to the Rescue is a 3-dimensional game with the ability to angle the camera in whichever direction will make it easiest to navigate for you. The player must bark at toys to short-circuit them, or roll into them to smash them.
Checkpoints within a level are places where the player will be sent back if you lose a life, and are marked by a parrot named Waddlesworth. If the player loses a life and have not reached a checkpoint, you will be sent back to the levels starting point. Unlike the Game Boy Color version of the game, toys the players break stay broken.
Each level has an 'animal friend' who will tell the player how to get through the level, and sometimes assign Oddball or Domino specific tasks to do in return for their help. Completing each of the Cruella levels will unlock a mini game to play.
- Level 1: Regent's Park: You start your journey here. Meet a squirrel named Fidget and help her take down Jasper and find her lucky nut.
- Level 2: Toy Store: Sergeant Tibbs (from the first movie) helps you through a toy store. Hop on the store's train to find a "secret room."
- Level 3: Piccadilly: You meet up with Fidget again. Turn the statues around in the circuit to get a surprise.
- Level 4: Big Ben: Ivana, a bat with allergies, helps you get to the top of London's famous clock tower.
- Level: Cruella I: Cruella is attempting to catch you and prevent you from starting the "Barking Chain." Use pineapples on catapults (and extra help from the tower's bell) to force her into submission.
- Level 5: Royal Museum: Cruella's dog Fluffy asks for your help to retrieve several misplaced artifacts (plus a jelly donut) and give you a heads up about one of her henchman.
- Level 6: Underground: A friendly rat named Chester helps you through the Underground (starting at a London subway station).
- Level 7: Carnival: Enjoy the rides at a carnival. You also run into Jasper, meet a fortune teller, and a turtle named Toby.
- Level 8: Lumber Mill: Chester shows up again (he is visiting a cousin named Nigel) and leads you through a dangerous lumber mill, filled with mean bulldozers, tanks, and many more of Cruella's toys.
- 'Level: Cruella II: You are trapped in a small pen with watermelons as you are terrorized by Cruella via boat. Use the watermelons to beat her.
- Level 9: Countryside: Ah, a peaceful terrain in the early morning. Meet a mole named Manny as he gives you tips on how to defeat the henchman in this level (fun fact: Stonehenge appears).
- Level 10: Barnyard: Uh, oh, the gate is locked! But fear not: a pig named Priscilla has you do chores in exchange for the gate to be opened. Please do not forget that today is her birthday, though.
- Level 11: Ice Festival: Enjoy the winter wonderland as you meet a snow bunny named Crystal, shoot down toy biplanes, and have another run-in with Jasper.
- Level 12: Ancient Castle: Ivana returns to help you out through a medieval castle.
- Level: Cruella III: Cruella is determined to stop you. Beat her using a catapult and pumpkins.
- Level 13: Spooky Forest: Crystal returns to help you through the forest. Watch out; Le Pelt is back!
- Level 14: Hedge Maze: Manny returns to give you tips on how to get through a hedge maze that stands in front of Cruella's mansion.
- Level 15: de Vil Mansion: Sergeant Tibbs is back to help you take down Horace.
- Level 16: Toy Factory: Fluffy is there to get you through this crazy place so you can get to Cruella.
- Level: Cruella IV: This is the final level; defeat Cruella and you win the game.