John Candy portrays Buck Russell, the main character in the movie who is a fun-loving and childish uncle that takes on the responsibility of caring for his nieces and nephew.
Jean Louisa Kelly plays Tia Russell, the rebellious teenage niece of Buck who initially clashes with his unconventional ways.
Gaby Hoffmann stars as Maizy Russell, the youngest and most innocent niece who forms a sweet bond with her uncle Buck.
Macaulay Culkin takes on the role of Miles Russell, the intelligent and mischievous nephew who tests Buck's patience.
Amy Madigan portrays Chanice Kobolowski, Buck's girlfriend who offers support and stability in his chaotic life.
Elaine Bromka plays Cindy Russell, Buck's sister and the mother of Tia, Maizy, and Miles, who entrusts Buck with caring for her children.
Garrett M. Brown appears as Bob Russell, Buck's brother-in-law and the father of Tia, Maizy, and Miles.
Laurie Metcalf portrays Marcie Dahlgren-Frost, a snobbish neighbor who disapproves of Buck's unorthodox methods but eventually warms up to him.
Jay Underwood plays Bug, Tia's crush who makes a brief appearance in the movie.
Brian Tarantina stars as E. Roger Coswell, a slimy and untrustworthy character who causes trouble for Buck and the family.
Mike Starr appears as Pooter-the-Clown, a clown hired for Maizy's birthday party but who ends up causing chaos.
Suzanne Shepherd plays Mrs. Hogarth, a nosy and judgmental neighbor who is wary of Buck's unconventional ways.
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