In a dystopian near-future Japan, a devastating dog-flu virus wreaks havoc among the canine population. A brilliant scientist named Professor Watanabe (Akira Ito) is on the verge of discovering a cure, but he faces immense opposition from the authoritarian Mayor Kobayashi (Kunichi Nomura), who decrees that all dogs must be exiled to the desolate Trash Island. Among the first to be banished is Spots (Liev Schreiber), a beloved pet belonging to Atari Kobayashi (Koyu Rankin), the orphaned nephew and ward of the mayor.
Atari lost his parents in a tragic accident and was adopted by Kobayashi on live television, yet his life in the mayoral household resembles that of a prisoner. In a heartwarming bond, Atari and Spots develop a deep connection as master and dog, infuriating Mayor Kobayashi in the process. The Kobayashi family has a notorious history of suppressing dogs, dating back a millennium to a time when their ancestor, a cat enthusiast, set out to obliterate canines from Japan. However, a legendary figure emerged to sever the tyrant's reign and secure the safety of dogs within the nation.
Fast forward six months, Atari courageously commandeers a plane and embarks on a daring journey to Trash Island in search of Spots. Following a crash-landing, he is rescued by a ragtag group of dogs led by Chief (Bryan Cranston), who is initially hesitant to warm up to humans due to his prior life as a stray. Despite this reluctance, the dogs rally together to fend off a rescue team dispatched by Mayor Kobayashi. With the encouragement of the lovely Nutmeg (Scarlett Johansson), a refined purebred, Chief gradually embraces his role to assist Atari.
To aid in their quest, they consult two wise dogs, Jupiter (F. Murray Abraham) and Oracle (Tilda Swinton), who caution them about the cannibal dogs inhabiting a remote corner of the island. In parallel, Professor Watanabe uncovers the long-awaited cure but is tragically poisoned by Kobayashi. An American exchange student named Tracy Walker (Greta Gerwig) grows suspicious of the corrupt dynamics at play and begins her investigation. She ultimately encounters Watanabe's former associate, Yoko Ono, who further validates Tracy's concerns and hands over the last remaining dose of the cure.
During their relentless pursuit, Atari and Chief find themselves separated from their group. In a touching moment, Atari bathes Chief, unveiling that his fur is actually white, triggering a poignant realization: Chief shares a rare lineage with Spots. As the two continue their journey, their bond deepens. They eventually reunite with their peers only to discover the rumored cannibal tribe, leading to a confrontation with Kobayashi's henchmen. Just in time, Spots arrives with a brigade of dogs to defend them and reveals that he has become the leader of the misunderstood tribe.
With the serious threat of extermination looming over Trash Island, Tracy's relentless investigations come to a head during Kobayashi's election ceremony. As Mayor Kobayashi prepares to carry out his sinister orders, Tracy presents her damning evidence of his corruption, while Atari and the dogs substantiate the effectiveness of the cure. Though Kobayashi seems to waver, Major Domo (Akira Takayama) insists on proceeding with the extermination. A chaotic battle unfolds, resulting in a backfire of the poison on the captors through the efforts of Tracy's tech-savvy friend.
In the tumult, both Atari and Spots suffer severe injuries, pushing Atari's remaining kidney to its limits. In a surprising turn of redemption, Mayor Kobayashi donates his own kidney to save Atari's life. Following the dire events, election laws dictate that the mayor's position now belongs to Atari, who promptly commands that dogs be welcomed back into society. As the story concludes, Atari and Tracy form a romantic bond, while Chief reunites with Nutmeg and takes on the role of protector for Atari. Though presumed dead, Spots emerges alive and secretly cares for his litter under the cover of the Kobayashi Manor.
