In a city called Ohkay, a villainous orange cat named Petey pounces on the peace of the town, hatching a plan to plant a bomb that could wipe out an abandoned warehouse. On the scene, the celebrated police officer Knight arrives with his loyal dog Greg to defuse the threat. In a deadly misstep, Knight cuts the wrong wire and the device explodes, taking Knight’s life by a head injury and leaving Greg paralyzed. Surgeons perform a miraculous procedure, transplanting Greg’s head onto Knight’s body and rebranding him as Dog Man. Almost instantly, Dog Man earns affection in the city for his relentless arrest of Petey, but no matter how many times Petey is captured, he always seems to slip away again. The loss of Knight weighs heavily on Dog Man, and the loneliness only deepens as his girlfriend Alice leaves, selling the couple’s house. With only a tennis ball from his former life as a memory, Dog Man retreats to a doghouse on the city’s outskirts, feeling the ache of a world that has moved on without him.
Meanwhile, Petey’s schemes take a darker turn as he decides to clone himself to create an assistant who mirrors him. The result is a newborn copy who, unlike his creator, lacks any evil drive and is named Li'l Petey. Petey steals the corpse of an evil telekinetic fish named Flippy with a plan to resurrect him using the Living Spray and to defeat Dog Man, but Li'l Petey’s presence complicates everything. In a bold move, Petey abandons Li'l Petey in the middle of the city in a simple cardboard box, hoping to rid himself of the burdens of his own offspring. However, Dog Man finds Li'l Petey and decides to adopt him, and the two begin to form a genuine bond in Dog Man’s home.
Hidden in his lair, Petey discovers a picture book drawn by Li'l Petey that imagines both of them as a family. The image fills Petey with guilt, especially once he learns that Li'l Petey was adopted by Dog Man. Using his orb-shaped mech, 80-HD, Petey retrieves Li'l Petey, but Dog Man notices Li'l Petey is nowhere to be found and, together with intrepid reporter Sarah Hatoff, begins a search for him. Their pursuit reveals that Li'l Petey has vanished, and the plot thickens around Petey’s backstory: Li'l Petey explains that his own father, who he calls Grampa, abandoned Petey as a child. In a bid to comfort Li'l Petey, Li'l Petey channels 80-HD to pull Grampa into the lair, where Grampa immediately starts berating Petey, underscoring that his ways have not truly changed.
In the city, Flippy is brought back to life at the Living Spray factory after a mishandling incident by workers, and the factory itself seems to awaken. Flippy is reprogrammed by Petey to target all good people, setting off a dramatic clash with Dog Man and friends as they fight an army of buildings animated by the Living Spray. Faced with the consequences of his actions, Petey experiences a moment of remorse and chooses to join forces with Dog Man, swapping Li'l Petey inside 80-HD for himself. The turn of events leads Flippy to the brink of ruin, and, in a moment of redemption, he decides to punish Petey by dropping him into an active volcano. Yet Li'l Petey arrives with a comic book that portrays them as friends, and the act of friendship redeems Flippy, stripping him of his telekinetic powers and allowing him to disable Petey’s plan.
With Flippy now neutralized, Dog Man seizes the chance to rescue the situation. He uses his trusty tennis ball to knock Petey away from the lava’s edge, and Flippy is successfully arrested. The city, impressed by the turn of events, pardons Petey, but he refuses to be seen as a reformed good guy. Returning to his lair, he finds Grampa has taken almost everything—except for Li'l Petey’s books. A quiet conversation with his clone inspires Petey to rethink his life and to pursue a more shared arrangement, deciding to share custody of his son with Dog Man. Petey also gifts his son a new ball, a small symbol of a new outlook, and heads back to his lair with a renewed sense of purpose, ready to face the future with Li'l Petey by his side.
