Als ihr kleiner roter Welpe zu einem knapp acht Meter großen Riesen heranwächst, versucht ein Mädchen mit ihrem Onkel, ihr neues Haustier vor einem bösen Gen-Konzern zu beschützen.
Lester and Orville accidentally launch a rocket which is supposed to fly to Mars. Instead it goes to New Orleans for Mardi Gras. They are then forced by bank robber Mugsy and his pal Harry to fly to Venus where they find a civilization made up entirely of women, men having been banished.
Fearing that he costs too much to feed, Clifford decides to join a traveling carnival so he can enter a talent contest in hopes of winning a lifetime supply of Tummy Yummies treats. Joined by his friends Cleo and T-Bone, Clifford meets up with Shackleford the High-Flying Ferret and Rodrigo Chihuahua of Steel, as they work together to turn a broken-down act into a record-breaking show.