As middle schooler Emily Elizabeth struggles to fit in at home and at school, she discovers a small red puppy who is destined to become her best friend from a magical animal rescuer. When Clifford becomes a gigantic red dog in her New York City apartment and attracts the attention of a genetics company who wish to supersize animals, Emily and her clueless Uncle Casey have to fight the forces of greed as they go on the run across New York City and take a bite out of the Big Apple. Along the way, Clifford affects the lives of everyone around him and teaches Emily and her uncle the true meaning of acceptance and unconditional love.