In the two years since his last adventure, Stuart Little (Fox) has blossomed and settled nicely into his new life. He goes to school (in his very own car), is very handy when it comes to building model airplanes and is proud of the fact he made the soccer team. And he loves having a big brother, George (Lipnicki) and a new baby sister, Martha Little to play with. Even Snowbell (Lane), the curmudgeonly cat with an attitude, has warmed up to Stuart in his own way.

Even still, Stuart yearns for a friend of his own – someone like him. Driving home from school, Stuart hears a loud squawk and suddenly an injured bird falls out of the sky, landing in the passenger seat of his car. When she regains consciousness, the mysterious bird introduces herself as Margalo (Griffith). She tells Stuart she is being threatened by Falcon (Woods), a feared crime lord who terrorizes all creatures living in Manhattan.

Stuart invites her to stay at the Little’s home and she is welcomed by all, even Snowbell. But when she mysteriously vanishes, the unlikely duo of Stuart and Snowbell set out on a heart-pounding, hair-raising journey to find her.