In a dystopian near-future Japan, a dog-flu virus spreads throughout the canine population. Though one scientist, Professor Watanabe (Akira Ito), is close to finding a cure, but overruling him the authoritarian mayor of Megasaki City, Kobayashi (Kunichi Nomura), signs a decree banishing all dogs to Trash Island. The first exile is Spots (Liev Schreiber), who belonged to Atari Kobayashi (Koyu Rankin), the orphaned nephew and ward of the mayor.Atari had lost his parents in a tragic accident and Kobayashi adopted him on live TV. But Atari was treat a little more than a prisoner in the Mayoral household, with Spots being his 24 hr guard dog. But Atari and Spots started loving each other as Master and Dog, angering Kobayashi. Historically, the Kobayashi family has been shown to fight the dogs for the last 10 centuries. Back then the Head of the Kobayashi family was a cat lover and had took upon himself to eradicate the canines from Japan. But A wonder boy was born who cuts off the head of the head of Kobayashi family and restores security of dogs in all of Japan, where they thrive under human protection ever since.Six months later, Atari steals a plane and flies to Trash Island to search for Spots. After a crash-landing, he is rescued by a pack of dogs led by a black dog, Chief (Bryan Cranston). They decide to help Atari locate Spots, although Chief, a former stray, is reluctant to fraternize with humans. They fend off a rescue team sent by Kobayashi to retrieve Atari. At the insistence of a female pure-breed named Nutmeg (Scarlett Johansson) (Chief has a huge crush on Nutmeg and will do anything to impress her), Chief reluctantly decides to accompany the group on their search. They seek advice from two sage dogs, Jupiter (F. Murray Abraham) and Oracle (Tilda Swinton), who warn them of cannibal dogs on an isolated part of the island.Professor Watanabe finds a cure, but is poisoned by Kobayashi. American exchange student Tracy Walker (Greta Gerwig) suspects a conspiracy and begins to investigate. She confronts Watanabe's former colleague Yoko Ono (Yoko Ono), who confirms Tracy's suspicions and gives her the last dose of the cure. During the journey, Atari and Chief are separated from the others. Atari bathes Chief, revealing that his coat is actually white. Noticing the similarity between Chief and Spots, Atari realizes that Chief is of Spots' breed, which is extremely rare. Chief recalls being part of a litter where all but one of his siblings died. He begins to bond with Atari as they continue their journey. They rejoin the group and locate the cannibal tribe, but are ambushed by Kobayashi's men. Spots arrives with an army of dogs who fend off the assailants. He reveals that he was rescued by the cannibal tribe (who were simply misunderstood and weren't cannibals at all) and became their leader. Spots also confirms that Chief is his brother and asks to transfer his protection duties for Atari to Chief, to which both agree.An owl brings word that Kobayashi plans to order total extermination of all dogs on Trash Island. At Kobayashi's election ceremony, Kobayashi prepares to give the order, but Tracy presents her evidence of his corruption. Atari and the dogs also arrive and confirm the cure works. Kobayashi has a change of heart, but his right-hand man Major Domo (Akira Takayama) insists on triggering the extermination. A fight ensues in which the "execute" button is pressed, but the poison backfires on the captors due to Tracy's hacker friend.During the fight, Atari and Spots are gravely injured. Atari's only remaining kidney fails, but Kobayashi, admitting his mistakes, donates his own to save him. By election law, mayor-ship of the city falls to Atari and he decrees that dogs be allowed to reintegrate into society. Tracy and Atari become a couple, and Chief reunites with Nutmeg and takes up the role of bodyguard for Atari. Presumed dead, Spots recovers and secretly raises his litter under the Kobayashi Manor.