Egun batean, Little familiak Stuart adoptatzen du, seme bat balitz bezala tratatzen duten sagu txiki bat. Littletarrak oso pozik daude Stuarten izaerarekin, baina Georgek, bere seme nagusiak, ez daki zer egin bere "anaia berriarekin". Bestalde, Snowbell, familiako katua, Stuart betiko etxetik botatzeko plan bat prestatzen ari da.

Stuart, an adorable white mouse, still lives happily with his adoptive family, the Littles, on the east side of Manhattan's Central Park. More crazy mouse adventures are in store as Stuart, his human brother, George, and their mischievous cat, Snowbell, set out to rescue a friend.