In 1885, a young Russian mouse named Fievel is separated from his family during a stormy sea voyage to America. He washes up in New York City and embarks on a quest to find his family, teaming up with a street-smart Italian mouse named Tony and a group of immigrant mice fighting against the city's cats. Along the way, Fievel encounters con man Warren T. Rat, who sells him to a sweatshop, and meets Irish mouse Bridget, who helps him escape and join the mouse rally against the cats. Fievel's family, who have also arrived in America, attend the rally but fail to recognize him onstage. The mice launch their plan to take over an abandoned museum, but Fievel gets lost and discovers Warren's lair, where he learns that Warren is actually a cat in disguise.

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Some movies that have similar genres and were produced around the same time as An American Tail include The Wizard, The Old Curiosity Shop, The NeverEnding Story, The Karate Kid Part III, The Bear, The NeverEnding Story II: The Next Chapter.