In 1947, cartoon characters are commonly referred to as "toons" and most work as paid actors in Hollywood. They frequently interact with humans and animals, and dwell in the animated district of Toontown, owned by businessman Marvin Acme. Amongst the toon stars is Roger Rabbit, who does comedy shorts with Baby Herman, but as of late his performances are poor. Meanwhile, R.K. Maroon, Roger’s employer and head of Maroon Studios, hires private detective Eddie Valiant to investigate rumors that Roger’s wife Jessica Rabbit is having an extramarital affair. Eddie himself is an alcoholic, following the murder of his brother Teddy at the hands of a toon. Going to the Ink & Paint Club, Eddie at first believes that Jessica is a rabbit (due to her last name), but surprised when he sees that she's a very attractive woman. He later attempts and manages to snap photographs of Marvin Acme playing patty cake with Jessica, showing them to Maroon and a distraught Roger who vows he and his wife will be happy, before running off.
Eleanor Little (Geena Davis) and Frederick Little (Hugh Laurie) go to the orphanage to adopt a younger brother for their son George (Jonathan Lipnicki). At the orphanage, they meet and fall in love with an anthropomorphic mouse named Stuart (voiced by Michael J. Fox). Despite misgivings from Mrs. Keeper (Julia Sweeney), they adopt Stuart and take him home. However, Stuart is greeted coldly by George, who refuses to acknowledge the mouse as his brother, and the family cat Snowbell (Nathan Lane), who disapproves of having a mouse for a "master".
Three years after the first film, Stuart questions his ability after a grueling soccer match alongside George, who kicked him with a soccer ball. He becomes even more downhearted after George's model airplane gets broken in an accident because of him. However, Stuart's father, Frederick Little, tells him that for every Little, there is a "silver lining", a good thing that comes out of an apparently bad situation.
When once-wealthy string magnate Rudolf Smuntz (William Hickey) dies, he leaves his outdated string factory and a run-down mansion to his two sons, Lars (Lee Evans) and Ernie (Nathan Lane). When Lars refuses a proposal by representatives from the large Zeppco conglomerate to purchase their string factory, his greedy wife April (Vicki Lewis) promptly throws him out. Meanwhile, Ernie serves Mayor McKrinkle (Cliff Emmich) at his restaurant in anticipation of becoming a famous chef for serving such a high-profile guest. However, the mayor is poisoned by a cockroach (which came from Rudolf's old box of Cuban cigars that Ernie took for himself) and suffers two heart attacks. As a result, the mayor dies, Ernie's restaurant is closed down by the Board of Health, and he too is out on the street.
Le film est composé de sept séquences illustrant huit morceaux de musique classique, réorchestrés et dirigés par le chef d'orchestre Leopold Stokowski à la tête de l'Orchestre de Philadelphie. La dernière séquence illustre deux morceaux et un intermède sépare la séquence 4 et 5. Chaque séquence est précédée d'une courte introduction où l'orchestre est en ombre chinoise.
Several years after settling in to their new home in The Bronx, New York, the impoverished Mousekewitz family soon finds that conditions are not as ideal as they had hoped, as they find themselves still struggling against the attacks of mouse-hungry felines. Fievel spends his days thinking about the wild west dog-sheriff Wylie Burp, while his sister, Tanya, dreams of becoming a singer. Meanwhile, Tiger's girlfriend Miss Kitty leaves him to find a new life out West, remarking that perhaps she's looking for "a cat that's more like a dog."
In London, circa 1897, a young mouse named Olivia Flaversham is celebrating her birthday with her toymaker father, Hiram. Suddenly, Fidget, a bat with a peg leg, barges in, and after a brief struggle, disappears with Hiram. Fidget takes Hiram to Professor Ratigan who commands him to create a clockwork robot which mimics the Queen of the Mice so Ratigan can rule England. Hiram initially refuses to participate in the scheme, but agrees when Ratigan threatens Olivia.
A human girl opens her car's door and throws a toy to the walkside, making out to her cat. This one, realizing that he has been abandoned by her owner, looking for a refuge when a storm explodes, comes to an old house with fame of cursed in the neighborhood. Trying to escape from it, he is threaten by a white rabbit called Jack and a white mouse called Maggie, ordering him to leave the house before Zoltar's see him. Zoltar, an nice and old magician, finds the cat and he decides to adopt him, putting the name of Thunder after his fear to the storm.
Le soir de Noël, l'égoïste et acariâtre Ebenezer Scrooge reçoit la visite du fantôme de son ancien associé, Jacob Marley. Celui-ci tente de le convaincre de l'immoralité de son métier d'usurier. Jacob lui-même, qui « escroquait les veuves et grugeait les pauvres », montre à Ebenezer les lourdes chaînes qu'il est condamné à porter « pour l'éternité… et peut-être même au-delà ». Jacob menace Ebenezer de la damnation s'il ne revient pas à une conduite plus morale.
Mrs. Brisby, a timid widowed field mouse, lives in a cinder block with her children in a field on the Fitzgibbons' farm. She prepares to move her family out of the field as plowing time approaches, but her son Timothy has fallen ill. She visits Mr. Ages, another mouse and friend of her late husband, Jonathan, who diagnoses Timothy with pneumonia and provides her with medicine. Mr. Ages warns her that Timothy must stay inside for at least three weeks or he will die. On her way home she encounters Jeremy, a clumsy but friendly crow. They both narrowly escape from the Fitzgibbons' cat, Dragon.
Celestine is a young mouse who lives in the underground world of rodents. At the orphanage where she lives, the caretaker known as the Gray One tells scary stories about the evil nature of the bears that live in the outside world, though Celestine doubts they are entirely true. She loves to draw but must soon study dentistry, since that's what all rodents do, and to prepare, she must travel above ground to collect bear cubs' lost teeth from underneath pillows. On one such occasion, the cub's family catches Celestine in the act and chase her into a trash can where she is trapped and spends the night. The next morning, a destitute and starving bear named Ernest discovers Celestine and attempts to eat her. Celestine convinces him to let her go by helping him break into the basement of a candy shop, where he can eat his fill. He is soon caught by the store's owner, however, and arrested. Celestine, who is behind on her quota of collected teeth, agrees to free him from the police wagon if he will help her break into and rob the teeth from the office of the store owner's wife, who happens to be a dentist.
Tom and Jerry together with their owners are about to move to a new home. The moving van is at their old house waiting, and Tom doses in the back of the car. However when he notices Jerry he puts him on a stick, and Jerry, noticing no escape and knowing that he will fly, he grabs hold of Tom's whiskers so they fly together into the garden. Jerry quickly dashes into his mousehole and locks the door, Tom nailing wooden planks on the door. When Tom tries to get in the moving car, he ends up with a bulldog and ties up his ears so he cannot see. Tom runs into the house for safety and stays there for the night.
Mickey Mouse pilots a river steamboat, suggesting that he himself is the captain. He cheerfully whistles "Steamboat Bill" and sounds the boat's three whistles. Soon the real captain appears (Pete) and angrily orders Mickey off the bridge. Mickey blows a raspberry at Pete, and then Pete attempts to kick him but Mickey rushes away in time and Pete kicks himself in the rear accidentally. Mickey rushes down the stairs, slips on a bar of soap on the boat's deck and lands in a bucket of water. A parrot makes fun of him, and Mickey throws the bucket over the bird.
Mickey est le machiniste d'un train dont la locomotive est anthropomorphe. Il commence le film en nourrissant plusieurs personnages, le train avec du charbon, son chien puis lui-même. Minnie Mouse, installée dans le dernier wagon, rejoint Mickey à l'avant et joue un morceau au violon sur lequel il danse. Après le repas, le train a du mal à gravir une colline et malheureusement le wagon de Minnie se détache... finalement Mickey réussit à le rejoindre et après cet incident, il repart sur les rails avec Minnie ...