In a bustling New York City neighborhood, Emily Elizabeth, a lonely middle schooler, struggles to fit in at her prestigious school. Her life takes an unexpected turn when her whimsical uncle Casey comes to babysit, and they visit a magical animal rescue tent run by the mysterious Mr. Bridwell. Here, Emily finds herself enchanted by a small red puppy. Despite being unsure if she can keep him, Emily names him Clifford, only to discover the next morning that the tiny pup has grown several feet tall overnight. With her mother's absence on a business trip, Emily and Casey must navigate hiding Clifford while scrambling to keep their normal lives intact as much as possible.

As they try to adapt to life with a giant, overly clumsy dog, the trio soon captures the attention of a genetics company, Lyfegro, led by the unscrupulous Tieran, who sees Clifford as a lucrative opportunity. Their interest forces Emily, Casey, and their tech-savvy neighbor Owen into a series of adventurous escapades across New York City to keep Clifford out of Lyfegro's clutches. Along the way, Emily and Clifford form an unbreakable bond, teaching her the importance of courage, family, and self-acceptance. The group must rely on creativity and teamwork to overcome obstacles, dodge threats from the nefarious corporation, and ensure that Clifford remains safe, using their hearts and wit in the sprawling metropolis where anything seems possible.