In 1890, five years after emigrating to the United States, the impoverished Papa Mousekewitz and Mama Mousekewitz lead their children, Fievel Mousekewitz and Tanya Mousekewitz, through a world where danger from cat-hungry predators still stalks their tiny homestead. Fievel dreams of something braver than fear, quietly thinking about a legendary bloodhound-sheriff, Wylie Burp, while Tanya nourishes ambitions of a life on stage. Meanwhile, Tiger’s girlfriend, Miss Kitty, leaves him to seek a wilder life out west, quipping that she’s searching for “a cat that’s more like a dog.”
A British aristocratic cat named Cat R. Waul launches an attack on the mice, forcing them to flee into the sewers. There, they meet a cow-boy mouse who is, in fact, a marionette controlled by Waul, who tricks the mice into moving further west. Tiger attempts to catch up with his friends but is diverted by a pack of dogs. On a train, Fievel overhears Waul’s grim plan to eat the mice. After being discovered, Waul’s hench-spider, Chula, strands Fievel in the desert. Devastated by the loss, the Mousekewitz family arrives in Green River, Utah.
In Green River, Chula blocks the water tower, drying up the river. Waul approaches the mice with a proposal to build him a new saloon, intending to use their labor and then consume them. Meanwhile, Fievel and Tiger drift separately through the wasteland; they mistake each other for mirages. Tiger is captured by a local mouse native tribe and hailed as a god, while Fievel is swept up by a hawk, only to be rescued when the natives attack and he falls into their village, where he reunites with Tiger. Tiger chooses to stay, while Fievel finds a way to Green River via a passing tumbleweed and re-joins his family, though they remain blissfully unaware of Waul’s scheming. At the saloon, Fievel overhears Waul’s plans in more detail and is discovered again by Waul, who tries to eat him but is distracted when he hears Tanya singing. He sends Tanya to Miss Kitty, who has become a saloon-girl cat and reveals she came at Waul’s request. Waul orders Miss Kitty to put Tanya on stage, where Tanya performs for the cats. Meanwhile, Fievel is captured by Chula and taken prisoner, but escapes.
Despondent, Fievel speaks with an elderly bloodhound sleeping outside the jail, discovering he is actually Wylie Burp. The old dog explains that he feels he has grown too old to be effective, but he agrees to train Tiger as a lawman and as a dog. Though reluctant at first, Tiger embraces the idea that a new persona might win back Miss Kitty. They return to Green River to confront the cats, who attempt to spring a concealed giant mouse trap on the mice at sunset during the opening of Waul’s saloon. Tiger, Wylie Burp, and Fievel fight the cats, and Tanya’s singing helps guide the escape. Seeing the danger, Waul uses a giant revolver repurposed as a cannon to threaten the fleeing mice, but Fievel intercepts him just in time. When Chula takes Miss Kitty hostage, Tiger rescues her, and the heroes use the mouse trap as a catapult to hurl Waul and his gang out of Green River. The cats soar through the air and land in a mailbag, which a passing train snatches away, breaking the water-tower blockade and restoring the river’s flow.
Enamored by his new persona, Miss Kitty reunites with Tiger, while Tanya becomes a celebrated singer. The water tower flows again, bringing Green River back to life as thousands of flowers bloom. Fievel receives his sheriff badge from Wylie Burp, and, though he’s unsure at first, he learns from the seasoned dog that his journey as protector—and as a community’s guardian—is far from over.
