As Emily struggles to fit in at home and at school, she discovers a small red puppy who is destined to become her best friend. When Clifford magically undergoes one heck of a growth spurt, becomes a gigantic dog and attracts the attention of a genetics company, Emily and her Uncle Casey have to fight the forces of greed as they go on the run across New York City. 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.
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.
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.