Fievel dreams about Wylie Burp, a bloodhound sheriff, while Tanya, his sister, wants to be a singer. In the meantime, Miss Kitty, Tiger's girlfriend, departs from him in search of a fresh start in the West, speculating that she might be searching for "a cat that's more like a dog." Five years after leaving Russia to immigrate to the US, the poor Mousekewitz family still had difficulty fending off raids by hungry cats in 1890.
The mice are attacked by Cat R. Waul, a British aristocratic cat, and are forced to escape into the sewers. There, they encounter a cowboy mouse—actually, Waul's marionette—who connives to convince the mice to head west for their betterment of life. When Tiger finds the letter of Fievel moving west with his family, he tries to catch up with his friend, but some dogs divert him from his path. Meanwhile, Fievel took the train, and it started moving before Tiger could reach up. Tiger rushes and catches the train, but unfortunately, he is again stuck with a dog inside the train.
And it fell into the water when the train crossed the bridge. Fievel, his family, and the mice were happy heading west. Tiger was caught on a fishing net and thrown away, and then once again gets engaged with the dog, yet to face the troubles when it was trying to escape. Fievel hears the cats' plan to devour the mice when she slips inside the livestock car on the train. When Fievel is discovered, he tries to escape, but Waul throws him off the train and leaves him trapped amid the desert with his hench-spider, T.R. Chula. Similarly, the Tiger also gets abandoned in the desert. Fievel’s family is devastated by his passing and travels to Green River, Utah.
When Chula gets to Green River, he shuts off the water tower, causing their so-called river to dry up. Waul approaches the mice and suggests they work together to build a new saloon, but he wants to eat the mice after tricking them into doing most of the labor. In the meantime, Fievel and Tiger—who have also made their way west—ramble aimlessly through the desert, passing one another. But they each decide that the other is a figment of their imagination and go their separate ways. A local tribe of mice captures Tiger and worships him as a god. After being taken by a hawk and dumped over the aboriginal settlement, Fievel meets up with Tiger again.
Tiger decides to stay inside with local tribal mice for a while, as they get offended if Tiger eats and runs off since it's an ungodly thing. So Fievel catches a passing tumbleweed and travels to Green River. When he gets back to his family, they assume he is hallucinating because of the heat of the desert when he informs them about Waul's plans. Fievel hears the cats' scheme about the trap to turn them into a mouse burger once more as he enters the saloon, and Waul finds him again.
When Waul hears Tanya singing, he is prevented from eating Fievel. Waul is so impressed with Tanya’s singing. When Tanya visits Miss Kitty, who has transformed into a saloon-girl cat, she says she came at Waul's request. Tanya entertains the cats by performing on the stage when he orders Miss Kitty to do so. Chula pursues Fievel in the meantime and takes him prisoner, but Fievel escapes.
Fievel, dejected, talks to an old bloodhound who is sound asleep outside the jail and learns that the dog Fievel is talking to is Wylie Burp. Fievel makes an effort to get him to assist. Even though Wylie believes he has become too old to be the lawman he once was, he nevertheless decides to train Tiger to be a lawman so he may formally retire. At first hesitant, Tiger gives in to the idea that Miss Kitty could be won back with a new identity.
Wylie trains Tiger in all possible ways and turns him into a dog outside. Now Tiger is strong, steady, and afraid not to be the sheriff. They go back to Green River to battle the cats, who try to catch the mice at dusk when Waul's tavern opens by hiding a huge mouse trap. While Tiger, Wylie, and Fievel battle the cats, Tanya and Miss Kitty find the trap.
Tanya sprints over to the mice and uses her singing skills to assist in their escape. When Waul notices this, he turns a massive pistol into a makeshift cannon to shoot the running mice. But when Chula kidnaps Miss Kitty, the furious Tiger saves her, and the heroes use the mouse trap as a catapult to drive Waul and his cats out of Green River. Wylie, however, commands Fievel to block Waul's attacks. The cats take off and land in a mailbag, which is picked up and left by a passing train.
Miss Kitty and Tiger rejoin, fascinated by his new demeanor. Green River blooms with millions of flowers as Tanya rises to fame as a singer, and the water tower bursts with 1,000 gallons of water once more. After Wylie is discovered by Fievel outside the celebration, he gives him his sheriff's badge. Although Fievel isn't sure if he should accept it, he knows that his adventure isn't finished.
