A Jack Russell Terrier named Max enjoys life in a cozy New York City apartment with his beloved owner, Katie. When Katie is away, Max passes the time socializing with other pets in the building, including tabby cat Chloe, pug Mel, dachshund Buddy, and budgerigar Sweet Pea. However, everything changes when Katie decides to adopt a Newfoundland named Duke, sparking feelings of jealousy in Max. Determined to rid himself of Max, Duke attempts to abandon him in an alley, but a group of aggressive cats, led by the Sphynx cat Ozone, attack them, ripping off their collars and leaving them vulnerable to capture by Animal Control. Duke is terrified of the prospect of returning to the pound, fearing for his life.
Max and Duke find unexpected allies in a white rabbit named Snowball, the charismatic leader of "the Flushed Pets," a gang of discarded animals that harbor bitterness toward humans for abandoning them. In a bid to gain acceptance from the gang, Max and Duke feign disdain for humans, claiming they’ve "killed" their owners. However, their deceit is soon uncovered when Snowball realizes they are domesticated, forcing Max and Duke to flee the sewers and hilariously board a ferry to Brooklyn, unintentionally dispatching the viper that was to test their loyalty. Snowball, enraged, vows to bring them to justice.
While this is happening, Gidget, a lovestruck white Pomeranian with feelings for Max, discovers his absence and sets off on a mission to find him. Teaming up with a red-tailed hawk named Tiberius, who clumsily leads her to Ozone, Gidget persuades him to reveal what he knows about the missing dogs. She quickly rallies others including Mel, Buddy, Chloe, guinea pig Norman, and Sweet Pea. Their journey introduces them to Pops, an elderly Basset Hound who supports Gidget and her friends in their search for Max. However, they soon confront Snowball, who threatens their lives. During a chaotic chase, Norman is captured, but Gidget and the crew narrowly escape.
Meanwhile, Duke shares with Max heartbreaking memories of his previous owner, Fred, who adopted him as a puppy and cherished their time together. Tragically, Duke reveals that he was lost while pursuing a butterfly and was ultimately abandoned at Animal Control, as Fred never returned for him. In a desperate bid to reunite with Fred, they visit his home nearby, only to be met by the resident cat, Reginald, who informs them of Fred's passing. Overwhelmed with grief, Duke wrongly believes Max is trying to rid himself of him and lashes out at the new homeowners, prompting Animal Control to intervene. In a twist of fate, Duke's brave interference allows Max to escape, while he himself is captured.
Determined to rescue Duke, Max battles Snowball, who surprises everyone with his unexpected aggression. However, when Snowball's gang is caught, they must put aside their differences and join forces to rescue themselves. A thrilling scene unfolds as they commandeer a bus, crashing into the Animal Control van on the Brooklyn Bridge while holding up traffic. Just when things look dire, Gidget and her team arrive to assist, leading to an explosive climax where the van tumbles into the East River, all while Max tries desperately to free Duke from captivity. In an act of bravery, Snowball jumps into the river to hand over the keys to Duke's cage and help secure their escape.
In a heartwarming conclusion, the group returns to their apartment via a pig-driven taxi. Snowball and the Flushed Pets concoct a new scheme to rid the world of humans, but everything changes when a little girl named Molly adopts Snowball. Initially defiant, Snowball eventually succumbs to the joy of re-domestication. With their adventures behind them, the other pets proudly return to their owners, and Max and Duke joyously reunite with Katie, forever forging their bond.
