An American Tail is a game based on the animated movie of the same name. It consists of ten levels (six main ones, four bonus) based on scenes from the movie. Animated scenes from the film are used as cut-scenes. It tells the story how Fievel Mousekewitz and his family leave Russia for America. He becomes separated from his family when a storm hits the ship and eventually ends up in New York.

Believing in the American dream, they head to New York City by boat because "there are no cats in America, and the streets are paved with cheese." The hero, a little mouse named Fievel, is washed overboard in a storm, and his search for his family, who believe he is dead and therefore aren't looking for him, forms the bulk of the film. Once arriving in America, all mice immediately discover that there are indeed cats in America. They begin living in a typical late 19th century immigrant manner: working in a sweatshop, living in horrible conditions, being extorted by gangs and living in constant fear of being eaten.