A villainous orange cat named Petey constantly terrorizes Ohkay City, with one of his schemes involving planting a bomb to destroy an abandoned warehouse. Famed cop Officer Knight and his dog Greg arrive to defuse the bomb, but Knight cuts the wrong wire and it explodes, killing Knight by head injury and paralyzing Greg's body. The surgeons save Greg by transplanting his head onto Knight's body and rename him Dog Man. Dog Man inherits Knight's job and quickly becomes beloved for his repeated arrests of Petey, but Petey always escapes. Dog Man becomes lonely and depressed due to the loss of Knight and the abandonment of his girlfriend Alice, who sells their house. He takes a tennis ball he used to play with as his only memory of his former life and moves into a doghouse on the city outskirts.
After firing his assistant, Petey decides to clone himself to create an assistant just like him. However, it creates a newborn copy of him with no interest in evildoing, whom he calls Li'l Petey. Petey steals the corpse of an evil telekinetic fish named Flippy and plans to use Living Spray to resurrect him and defeat Dog Man, but Li'l Petey interferes. Petey decides to abandon him in a cardboard box in the middle of the city, where Dog Man finds and decides to adopt him. The two begin to bond as they spend time together in Dog Man's home.
At his lair, Petey discovers a picture book drawn by Li'l Petey depicting both of them as a family, making him feel guilty for abandoning him. Learning from his former assistant that Li'l Petey was adopted by Dog Man, Petey uses his orb-shaped mech, 80-HD, to retrieve him. Dog Man realizes that Li'l Petey is nowhere to be seen, and he and news reporter Sarah Hatoff begin to look for him, but they realize that he is gone. Meanwhile, Petey reveals to his "son" that his abusive father abandoned him as a child. In an attempt to cheer him up, Li'l Petey uses 80-HD to bring Petey's father, called Grampa by Li'l Petey, to his lair. Grampa immediately starts berating Petey, revealing that he has not changed despite Li'l Petey's hopes.
Flippy is resurrected at the Living Spray factory after being mishandled by the factory employees, which also causes the factory itself to come to life. Having been reprogrammed by Petey to destroy all good people, he targets Dog Man and his friends, who fight an army of buildings affected by the Living Spray. A remorseful Petey reluctantly decides to team up with Dog Man, swapping out Li'l Petey inside 80-HD with himself. Realizing that his reviver is redeemed, Flippy decides to drop Petey into an active volcano to kill him, but Li'l Petey arrives and shows him a comic book depicting them as friends, redeeming him and disabling his telekinetic powers, dropping Petey above the volcano. Dog Man uses his tennis ball to knock Petey from falling in the lava, and Flippy is arrested. Petey is pardoned by the mayor, but refusing to be considered a do-gooder, he and Li'l Petey return to their lair to find that Grampa took everything except for Li'l Petey's books. After a talk with his clone, Petey decides to share custody of his son with Dog Man, and gives him a new ball. He then heads back to his lair with a new outlook on life.
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