When middle-schooler Emily Elizabeth's (Darby Camp) fun but impulsive uncle Casey (Jack Whitehall) takes her to visit a magical animal rescuer (John Cleese). she meets a tiny red puppy and falls in love instantly. When she asks how big the dog will get, he responds that it depends on how much she loves him.

She names him Clifford, and although she expected him to grow, she didn't foresee waking up to find a giant ten-foot hound in her small New York City apartment. While her single mom (Sienna Guillory) is away on business, Emily, Clifford and uncle Casey set out on an adventure as they try to keep the overgrown dog out of trouble.