The film begins in the small Russian village of Shostka as the camera zooms in on the Moskowitz house. Then, the camera pans down to a tiny door marked Mousekewitz, the dwelling of a mouse family that includes Papa (voiced by Nehemiah Persoff), Mama (voiced by Erica Yohn), their son, Fievel (voiced by Phillip Glasser), their daughter, Tanya (voiced by Amy Green), and a baby, Yasha. Inside their tiny living quarters, Papa plays his violin while Mama takes care of the baby. Fievel comes running into the room asking about Hanukkah presents. Papa presents Tanya with a new babushka and gives Fievel a new hat (Papas hat that has been passed down from father to son for generations). The hat is far too big, but the boys mother tells him he will grow into it.
As part of their Hanukkah celebration, the Mousekewitz children encourage Papa to tell them the story of the Giant Mouse of Minsk, who was as tall as a tree and scared all the cats. Mama doesnt like even a mention of the word "cats," and asks them to talk about something else. The children want to hear about America, which Mama thinks is just another fairy tale, but Papa appears to drift off into a dream world as he talks about the opportunity of a new and better life in America where mouse holes are everywhere, bread crumbs are on every floor, mice can say anything they want, and, he knows for a fact, there are not cats.
Just then, they are attacked. Humans and mice run from their homes as the Cossacks attack the humans and their homes, while the "Catsacks" attack the mice and their dwellings. Brave little Fievel tries to scare the cats away by banging loudly on a skillet with a spoon, but he is chased and almost killed by the cats. Suddenly, the pogram is over and the Cossacks and Catsacks withdraw. Afterwards, as they survey the damage, Papa whispers, "In America, there are no cats." The scene shifts to a Hamburg, Germany shipyard where a band plays an oom-pah tune as the mice, including the Mousekewitz family, climb a rope to board a ship bound for America. Fievel creates problems with his wide-eyed wonder and constant questions. Once they are on board, the mice shout their goodbyes to the other mice on the pier as the ship departs. During the voyage, Papa plays his violin in the mouses small section of the ship away from the humans. Just like all children, Fievel asks, "Are we there yet?" Tanya is afraid theyve made a poor decision to travel to America, but Papa reassures her that everything will be all right as long as they stay together.
Later, Fievel discovers a barrel of herring and Papa tells him about even larger fish in the ocean. The mischievous boy wants to see them. When he tells his mother about the fish, she says theyre lucky they didnt see cats. The dreaded word causes all the mice to shutter. Papa reassures all his fellow mice passengers that America will be wonderful because there are no cats there. His statement leads the mice to tell horror stories of cats as they sing "There Are No Cats in America." After Papa sings a verse, all the mice join in the chorus; then, an Italian mouse sings about the cat problems in his country, after which the mice all joyfully sing the chorus; next an Irishman sings a verse, after which the mice celebrate and sing the chorus again.
Soon, a storm hits and the ship rocks, which causes a lot of seasickness. While Fievel is warming himself by the stove, a piece of burning coal burns his tail. When he jumps, he is washed him around the ship until he ends up at the bottom of the stairs leading to the deck. He is fascinated when a wave washes some fish down the stairs, so he climbs up to see more. Out on deck, he is overcome by the storm and the waves. Fievel imagines all sorts of sea monsters in the waves of the storm. After one particularly large wave, Fievel is washed overboard and the ship sails away into the storm.
The following scene is of Castle Gardens, the immigration depot in New York City. As both humans and mice go through immigration, they are given new American names. When the Mousekewitz family passes through they are sad that they are now a family of four not five. The immigration officials change Tanyas name to Tillie. Next, we see a small bottle flowing on the water. As a chorus sings "Give Me Your Tired, Your Poor," the words written on the Statue of Liberty, the audience sees Fievel inside the bottle. As he peers through the bottle, he sees the Statue is under construction. When the bottle washes ashore, a French pigeon, Henri (voiced by Christopher Plummer), who claims to be building the statue, discovers him. After Henri cleans up the little immigrant, Fievel talks despondently about the possibility that he will never find his family. Henri, in a Maurice Chevalier-type voice, boosts the boys confidence by singing "Never Say Never." Fievel and three female pigeons join in the song. Afterwards, Henri instructs one of the females to fly Fievel to immigration.
The next scene is the city, which is full of immigrants humans and mice and they are all being hustled by con artists. One of the slickest of the scoundrels preying on the unsuspecting newcomers is Warren T. Rat (voiced by John Finnegan). His constant companion is his cockroach accountant, Digit (voiced by Will Ryan).
Upset that he has made fifty cents less today than yesterday, Warren T. spies the innocent Fievel, introduces himself and claims he can take the boy to his parents. Fievel follows the rat anticipating the reintroduction to his family right away.
Meanwhile, at the Mousekewitzs new home, an old, discarded physicians bag, Tanya tells her parents that she has a feeling that her brother is still alive. Just as she looks out a window, Fievel and Warren T. pass unseen nearby.
When Warren T. takes Fievel into a building and opens a door, Fievel excitedly looks inside for his family. He is grabbed by a mean character named Moe (voiced by Hal Smith). Fievel has been tricked and is now in a workhouse or sweatshop. Warren T. reminds Moe to send Fievels salary to him. That evening, Fievel ties several sheets together and escapes by climbing down the sheets to the street. Tony Toponi (voiced by Pat Musick), an Italian immigrant mouse, gives Fievel an Americanized name, Philly. Once he is out of the workhouse, Fievel unknowingly walks right past his familys home in the doctors bag. As Fievel wanders the lonely streets, we hear "Poor Wand'ring One." Once, the boy hears someone calling his name, but its another mother calling her son named Fievel. Later, he hears someone playing a violin and thinks its his Papa. He is very disappointed to discover the sound is coming from an Edison cylinder recording. When the lady of the house changes the cylinder, Sousas march, "Stars and Stripes Forever" blasts from the speaker, which causes Fievel to fall into the player. The sight of a mouse frightens the lady who chases Fievel out a window.
After some more wandering, Fievel runs into Tony Toponi again, who volunteers to help find the kids family. At the same time, Tanya and Papa leave their home to search for Fievel and at one point, Tony and Fievel walk directly above Tanya and Papa and neither sees the other.
During their search, Tony and Fievel happen to pass a rally where a pretty Irish mouse, Bridget (voiced by Cathianne Blore), is trying to convince the other mice to organize in order to defeat the cats. Tony is immediately smitten with Bridget. While Tony gets acquainted with Bridget, Fievel tells the crowd they have nothing to fear because his Papa told him there werent any cats in America. Just then, from behind a crate, a cat pounces on Fievel and almost eats him. After a frantic chase where Fievel avoids becoming the cats meal, Bridget suggests she and Tony take Fievel to see Honest John (voiced by Neil Ross), a local politician, who knows all the mice in the city. Just as soon as Tony, Bridget and Fievel leave, the Mousekewtiz family emerges from under the rubble that is left from the cat attack. Mama sarcastically asks Papa, "there are no whats in America?" Papa sheepishly snickers.
When the new trio of friends arrives at Honest Johns, Gussie Mausheimer (voiced by Madeline Kahn), the richest mouse in the city, is also there to complain about the cat attack. She recommends a "wally" (Gussie cant pronounce "r"s) of all the mice, rich and poor, to decide a course of action against the cats. When Gussie leaves, Honest John is ready to help Fievel find his family until he discovers that the Mousekewitzs are too new in the country to be registered voters. He is only interested in helping if votes are his reward.
That night, Fievel sleeps in a water tower where Bridget lives. She encourages the boy and tells him she is certain his family is out there somewhere just waiting to be found. After Bridget leaves, Fievel gets out of bed, goes to a knothole in the wall, looks out over the city and, as the moon rises, sings "Somewhere, Out There." From her doctors bag home, Tanya joins Fievel in the song. They dream of reuniting their family.
At the rally in the park, Fievel is on the speakers stand with Bridget and Tony, while his family is in the audience, but once again, they dont see each other. Gussie delivers a stirring speech about coming to America for freedom freedom from cats. When she asks for ideas concerning a course of action, no one offers any suggestions until Fievel steps forward and whispers an idea into her ear. She smiles, whispers the idea to Honest John, and then announces to the crowd that they have a plan.
Early the following day, all the mice go to Dr. Digitalus Museum of the Weird and Bizarre, which is located on a pier. They collect various objects from the museum and begin to build a large contraption. Tony wakes up late, so he grabs Fievel out of his bathtub bed and they run towards the pier to help the other mice. Fievel has trouble keeping up, trips and falls into a sewer grate. When he thinks he hears his Papa playing his violin, Fievel drops down into the sewer and follows the music. He finally discovers the source of music in a place marked "Mott Street Maulers." The music is coming from a player piano and a violinist. Inside, a group of cats are playing poker. One of the cats is Tiger (voiced by Dom Deluise), a large orange cat, who is pretty dimwitted.
When the camera pans up to the music, the violin player is Warren T. Rat. Warren T. complains he cant play because of his nose, so he removes his false nose and ears, which reveals that he is really a cat. Fievel blurts out "He's a cat!" Warren orders the other cats to capture the intruder. Tiger tries to help, but is more trouble than help. A big chase ensues. Just when it seems Fievel has escaped again, a paw grabs him and pulls him back into the sewer.
Back at the museum, Gussie explains the plan to the other mice. They are going to scare the cats onto a ship that is bound for Hong Kong with the contraption they have built. Since the ship departs at 6 a.m., the mice must lure the cats to the pier at that precise time.
Fievel is being held prisoner in a birdcage in the sewer and is being guarded by Tiger. When Tiger finds out that Fievel lost his family, he empathizes because he lost his family too. We also learn that Tiger is a vegetarian cat. Once Fievel and Tiger become friends, they perform a song and dance routine together titled "A Duo." Digit, the cockroach, sees the prisoner and his guard frolicking together and tells his boss. Fievel manages to escape, so Warren T. fires Tiger.
Back on the street, Fievel heads to the pier with the cats right behind. Inside the museum, the mice are sleeping, but Fievels frantic screams wake them up. The cats are ten minutes early, but since the cats are there, the mice in charge of the secret weapon release it. Since it is too early, Honest John and some other mice finally stop it. In front of the museum, Tony shoots Warrens fake nose off exposing him as a cat. Then, Warren sets fire to the museum. Gussie, who is watching the clock, commands the secret weapon be released. Fievel grabs a piece of burning wood and burns the rope that is restraining the weapon. When it begins to move, it throws Fievel up against the wall and knocks him out. Out of the burning building the contraption, the Giant Mouse of Minsk (from the story Fievels Papa had told them), comes rolling down the pier and frightens the cats. They run down the pier, into the water and are lifted onto the departing vessel by the ships anchor.
During the mices celebration, Tanya hears Honest John say, "We owe it all to Philly." She asks Papa, "Who is Philly?"
Leaking kerosene causes the fire to spread and the pier is consumed in flames. Bridget and Tony look for Philly but all they find is his hat. Tanya hears them calling Philly and reminds her father that immigration changed her name to Tillie. She runs towards the calls; Papa and Mama follow. When they meet Tony, Mama recognizes Fievels hat. Fievel is revived by the firemens water hoses. The force of the water washes him through a hole in the floor. He ends up in Orphans Alley where he meets a group of street urchins who convince him to give up hope of ever finding his family. They tell him if his family really cared, they would have found him by now. Fievel cries himself to sleep.
The next morning when Fievel awakes, he hears someone calling his name, but he thinks it is just a dream. Gussie, Tony, Bridget, and his family are riding on Tiger searching for him. Fievel finally pays attention when he hears Papa playing his violin. When he shouts "Papa," his father hears him, jumps off of Tiger and runs towards his son for a happy reunion. The others soon join the celebration. Papa returns Fievels hat, which, to everyones amazement, fits. Papa says, "My son! Now, you are a mouse." The following scene shows Henri flying Fievel and Tanya to see his finished statue. Papa and Mama are flown by another pigeon and Tiger is transported by multiple pigeons. They all admire the Statue of Liberty. The statue even winks at Fievel and Tanya. Fievel asks Henri about all the other land they see from the air. He tells the boy that all of it is America. Fievel wants to see it. Henri assures him that he will someday. As Henri flies them away from the statue, Fievel and Tanya say "Goodbye."
The closing credits roll over drawings of the statue. Then, "Somewhere Out There" is heard again as performed by Linda Ronstadt and James Ingram.