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A thousand years ago, dogs roamed freely across the land. Their reign was cut short when the cat-worshipping Kobayashi Dynasty waged war against them, seeking their eradication. Hope emerged in the form of a young warrior who stood against the tyranny. With a single decisive strike, he decapitated the head of the Kobayashi Clan, bringing peace to the dogs and securing his legacy as the Boy Samurai of Legend.
In the year 2038, a devastating canine flu spreads through the metropolis of Megasaki. Under the rule of the authoritarian Mayor Kenji Kobayashi, a decree is issued: all dogs are to be exiled to Trash Island, a barren wasteland filled with refuse. Professor Watanabe, a leading scientist and Kobayashi’s political adversary, insists that he is close to finding a cure, but his pleas fall on deaf ears. The first dog cast away is Spots Kobayashi, a loyal bodyguard to 12-year-old Atari Kobayashi, the mayor’s distant nephew and orphaned ward.
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Six months later, Atari takes fate into his own hands. Hijacking a small plane, he crashes onto Trash Island, determined to find Spots. There, he encounters a pack of abandoned dogs—Rex, Duke, King, Boss, and their gruff stray leader, Chief. Together, they navigate the wasteland in search of Spots. When they discover what appears to be his remains in a locked cage, hope falters. Atari and the dogs fend off a retrieval squad sent by Mayor Kobayashi to capture the boy. Chief, reluctant to grow attached, initially refuses to aid Atari further, but Nutmeg, an elegant former show dog, convinces him otherwise. Seeking wisdom, they visit the island’s elder canines, Jupiter and Oracle, who suggest that Spots may be alive, held captive by an enigmatic tribe of rumored cannibal dogs.
Meanwhile, in Megasaki, Professor Watanabe succeeds in developing a serum that can cure the dog flu. He presents his findings to Kobayashi, but instead of embracing the breakthrough, the mayor orders his silencing. Major Domo, the mayor’s ruthless enforcer, ensures Watanabe’s assassination by lacing his sushi with poison. At the same time, Tracy Walker, an American exchange student and vocal activist for the pro-dog movement, begins to unravel a sinister conspiracy. She suspects foul play behind the outbreak and the exile and sets out to expose the mayor’s true agenda. With evidence mounting, she learns that Kobayashi and his ancestors orchestrated the extermination of dogs for generations and that this decree is merely the final act in a centuries-old vendetta.
Atari and Chief, separated from the rest of the pack, form an unlikely bond. A cleansing bath reveals that Chief, once thought to be a hardened stray, has a white-and-black-spotted coat, identical to Spots. The two reconnect with the others just as they are ambushed. Salvation comes in the form of Spots himself, alive and well. The lost bodyguard has become the leader of the tribal dogs, a group of former test subjects from an abandoned research facility. He has since taken on new responsibilities, including his mate, Peppermint, who carries their first litter. Recognizing Atari’s bond with Chief, Spots entrusts his original duty as Atari’s protector to his younger brother. However, a grave warning reaches them—Kobayashi plans to eradicate every remaining dog with poison gas.
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Back in Megasaki, Tracy confronts Watanabe’s colleague, Yoko Ono, who confirms Tracy’s suspicions and provides her with the last vial of the cure. As Kobayashi prepares to execute his extermination order at his re-election ceremony, Tracy interrupts the proceedings, revealing his crimes to the public. Furious, the mayor orders her immediate deportation, but before he can act, Atari and his pack arrive, proving the effectiveness of the serum by curing Chief in front of the masses. Standing before the people, Atari delivers a haiku, evoking the once-sacred bond between humans and dogs.
Moved by his words, the people turn on Kobayashi, forcing him to revoke his decree. Enraged, Major Domo attempts to carry out the extermination regardless but is stopped by the combined efforts of the dogs and Tracy’s activists. In the chaos, Atari and Spots are gravely injured, and both are rushed to the hospital. In an act of redemption, Kobayashi donates one of his kidneys to save his nephew’s life. With the mayor disgraced and his crimes exposed, Atari is instated as the new leader of Megasaki.
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One month later, Megasaki is transformed. Dogs are welcomed back into society, cured of the flu, and reunited with their owners. Kobayashi and his co-conspirators are imprisoned for their crimes. Atari and Tracy grow closer, forging a new future together, while Chief and Nutmeg take their place as the young mayor’s trusted guardians. Meanwhile, Spots, now a father, watches over his growing family under the guidance of a Shinto priest, living in peace at last.