Eleanor and Frederick Little and their young son George are intending to adopt. While George is at school, his parents go to an orphanage where they meet an anthropomorphic teenage mouse named Stuart. Despite misgivings from Mrs. Keeper, they adopt Stuart and take him home. However, Stuart is greeted coldly by George, who refuses to acknowledge the mouse as his brother, and the family cat Snowbell, who is disgusted at having a mouse for a "master". Despite Eleanor and Frederick's intentions, Stuart quickly feels like an outsider in the large Little family, especially when their relatives bring Stuart large presents and George snaps at his family, claiming that Stuart is not his brother. When Stuart admits his feelings of loneliness to his parents, they ask Mrs. Keeper to do some background research on Stuart's biological family.
Three years after the first film, Stuart Little questions his abilities following a disastrous Association football match alongside his brother George, who accidentally kicked him with a Ball (association football) despite said kick scoring the winning goal for their team. Stuart's relationship with George is strained further after he accidentally crashes a model airplane they were working on in the city park. Stuart's father, Frederick, tries to encourage him, telling him that "every cloud has a silver lining (idiom)."
Stuart and his family (and Monty who stows away in the car) are going camping. When they get there, Stuart meets a smooth-talking skunk named Reeko, who is forced to give food to "The Beast" who is a cougar. Stuart and George join the "Lake Scouts," which Stuart has trouble in. But Reeko makes a deal with the Beast, resulting in Snowbell getting captured by her, and Stuart goes off on an adventure to save him. Eventually, Stuart and his friends attempt to trick the Beast into falling into a trap covered with sticks and leaves, which doesn't work. Reeko shows up with a group of forest animals. Reeko taunts the Beast, and the Beast roars at him. Reeko turns around, yells a battle cry, and sprays the Beast with all of his might. The Beast is taken away to a zoo, and Stuart earns a gold kerchief at last. Reeko tells Stuart that he (Reeko) was wrong to betray him. Stuart bids farewell to his friends as he, George, Eleanor, Frederick, Snowbell, and Monty head back home to New York.
Stuart Little is now an animated TV Series based on the original movie in which Stuart continues his life-long adventures.