Leonard Helperman (voice of SHAUN FLEMING) and Spot (voice of NATHAN LANE) are the best of friends, as they should be since Spot is Leonard's faithful canine companion. The only difference is that Leonard and his teacher mom, Mary Lou (voice of DEBRA JO RUPP), can understand him, as can fellow pets Pretty Boy (voice of JERRY STILLER), a gruff bird, and Jolly (voice of DAVID OGDEN STIERS), a soap opera loving cat.
Yet, Spot yearns to be a human boy, just like Pinocchio. He thinks he has a chance of obtaining his wish when he hears about a mad scientist, Dr. Ivan Krank (voice of KELSEY GRAMMER), who's experimenting with turning everyday animals into humans.
The only problem is that Krank - the crazy uncle of Leonard's classmate, Ian (voice of ROB PAULSEN) - lives in Florida, thousands of miles away. Fortunately for Spot, Principal Crosby Strickler (voice of WALLACE SHAWN) has nominated Mary Lou for a teacher of the year award and she and Leonard have just left for the Sunshine State ceremony.
With pet sitter Mrs. Boogin (voice of ESTELLE HARRIS) watching after Pretty Boy and Jolly, Spot concocts a wild story to convince Mary Lou to let him join them on their trip. Once in Florida, he meets Krank and some of his previous but not altogether successful experiments including Dennis (voice of PAUL REUBENS), the alligator boy, and half-girl, half mosquito Adele (voice of MEGAN MULLALLY).
Despite those failures, Spot has Krank put him through the transformation process. Unfortunately, none of them took into account the difference in dog vs. human years, resulting in Spot becoming the middle-aged Scott.
From that point on, and as Krank tries to recapture Scott/Spot for his own grandeur, the dog, his fellow pets and his human master try to figure out what to do.