Things are good on Birdwell Island where canines Clifford (voice of JOHN RITTER), Cleo (voice of CREE SUMMER) and T-Bone (voice of KEL MITCHELL) are best friends. Neither the latter two nor Clifford's young human owner, Emily Elizabeth Howard (voice of GREY DELISLE), seem to care or mind that he's a gigantic pooch, nearly as big as a house.
When the local carnival comes into town, the three dogs eagerly await Larry's Amazing Animals Show. Run by Larry Gable Gobble (voice of JUDGE REINHOLD), the act consists of Shackelford (voice of WAYNE BRADY) the trapeze flying ferret and Dorothy (voice of JENNA ELFMAN) the high wire cow who performs despite a fear of heights. Then there's Dirk (voice of JESS HARNELL) the laidback but daring dachshund who performs on rocket-powered skates and Rodrigo (voice of WILMER VALDERRAMA), the weightlifting Chihuahua.
Despite the show not really being that good, Clifford and his friends are impressed. Yet, Larry faces his act being shut down if something doesn't change. However, when Shackelford learns of an animal talent contest sponsored by the maker of the popular pet food Tummy Yummies, George Wolfsbottom (voice of JOHN GOODMAN), things begin to look up. That's especially true when he glances up - way up - to Clifford and realize the gigantic pooch is what they need to win.
Clifford isn't interested, however, until he overhears a human neighbor telling Emily's parents that the big pooch must be eating them out of house and home. Sad over learning that but determined to make things right, Clifford runs away from home and joins the carnival, hoping to help win the contest and the prize of a lifetime supply of Tummy Yummies.
As the newly expanded animal act rehearses their show, they must deal with various setbacks -- including Shackelford becoming jealous of Clifford unwittingly taking the spotlight away from him, as well as Wolfsbottom's spoiled daughter, Madison (voice of KATH SOUCIE), wanting Clifford all for herself -- that threaten to derail Clifford's plans.