A young girl's love for a tiny puppy named Clifford makes the dog grow to an enormous size.
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. Based on the beloved Scholastic character, Clifford will teach the world how to love big.
In New York City, 12-year-old Emily Elizabeth Howard struggles to fit in at her middle school. Bullied by a popular girl named Florence, Emily finds solace in her new friend Owen Yu. While Emily's English mother, Maggie, leaves for a business trip to Chicago, Emily is left in the care of her irresponsible uncle, Casey, who lives in a van.
One day, Emily stumbles upon an animal rescue tent run by the mysterious Mr. Bridwell at a local park. There, she meets a tiny red puppy whose family was taken by dogcatchers. Mr. Bridwell explains that the puppy's size will reflect how much love he receives. Although Emily falls in love with the puppy, Casey refuses to let her adopt him, citing the apartment building's no-pets policy. However, Emily later discovers the puppy in her backpack and names him Clifford. Casey reluctantly agrees to let Clifford stay for one night.
By the next morning, Clifford has grown to an enormous size. Emily and Casey try to hide him from their building's nosy superintendent, Mr. Packard. They attempt to take Clifford to the vet but chaos ensues when Clifford chases a man in an inflatable bubble and destroys the clinic's weight scale. Clifford's giant stature quickly goes viral online. Learning about Bridwell's reputation for performing miracles with animals, Emily and Casey set out to find him. Meanwhile, Clifford escapes Casey's truck and inadvertently humiliates Florence, earning Emily the attention and friends she always wanted.
News of Clifford reaches Zac Tieran, the unscrupulous owner of the biotechnology company Lyfegro. Hoping to save his failing business, Tieran falsely claims Clifford is a genetically engineered experiment and launches a citywide search to capture him. After being tipped off by Tieran, Mr. Packard evicts Emily and Casey. Refusing Tieran's bribe, they go on the run with Clifford in Casey's van. With help from their neighbors, they fend off Tieran's henchmen and take refuge at Owen's lavish apartment.
Casey promises Emily that Clifford can stay with her if they find Bridwell and he can shrink Clifford back to his original size. If not, Clifford will have to be sent to Owen's father's animal sanctuary in Shanghai. The trio tracks Bridwell to a hospital, only to discover that the man has supposedly passed away. Heartbroken, Emily reluctantly agrees to send Clifford to China. She bids him an emotional farewell as he sails away on a tugboat under the cover of night.
The next day, Tieran intercepts the ship, and Clifford is airlifted to Lyfegro headquarters for experimentation. Emily soon discovers that the Bridwell who died at the hospital was not the real one. With renewed hope, she and Casey, joined by their friends and neighbors, break into Lyfegro to rescue Clifford. After a daring escape through the city, Emily rides Clifford to Manhattan Bridge Park, where a crowd gathers to witness the spectacle.
There, Emily finds Bridwell and pleads for his help. Bridwell reveals that Clifford's size is a reflection of Emily's love and cannot be reversed. Instead, he encourages her to embrace Clifford's uniqueness and advocate for herself. Inspired, Emily speaks to the crowd, explaining the importance of love and acceptance, regardless of differences.
Tieran interrupts, demanding the police verify Clifford's ownership using a secret ID chip implanted in him. The chip identifies Emily as Clifford's rightful owner, and Tieran is fined for filing false claims and wasting police resources. Clifford is officially recognized as Emily's pet.
Emily and Casey reunite with Maggie, who returns just in time to witness the joyful conclusion. Mr. Packard reverses the family's eviction and appoints Clifford as his new assistant. Casey begins a new chapter by leaving his van behind and starting a career at Scholastic Corporation, writing and illustrating books based on Clifford's adventures. Together with their neighbors, Emily, Casey, and Maggie help build Clifford a giant doghouse, ensuring the big red dog remains a beloved part of their community.
