During the destruction of the planet Krypton, a Kryptonian Labrador Retriever comforts fellow infant survivor Kal-El as they head in an escape pod toward Earth.

Years later, now known as the famous superheroes Krypto and Superman, they live in the city of Metropolis under their dual identities Bark and Clark Kent. Clark is a reporter and journalist at the Daily Planet, a newspaper company, and dating Lois Lane, a fellow journalist whom Krypto is jealous of. Thinking that Krypto needs a friend to distract him, Clark heads to an animal shelter to find one. A Boxer named Ace tries to escape the shelter, but Krypto stops him. Later, Superman and Krypto spot their archenemy, LexCorp CEO Lex Luthor, reeling in a meteor strapped with orange kryptonite with a tractor beam, intending to gain superpowers. He is easily defeated as the two are aided by the Justice League.

Meanwhile, Lulu, a guinea pig test subject from LexCorp sent to the shelter, reels in a piece of orange kryptonite with her own tractor beam, which gives her flight and telekinesis. Unbeknownst to her, everyone else in the shelter also gains superpowers. Ace is now super-strong and indestructible; PB, a potbellied pig, can change size; Merton, a nearsighted turtle, becomes super fast; and Chip, a squirrel, gains electrokinesis. While at home, Superman and Krypto have an argument when the former plans to propose marriage to Lois. However, Clark is captured by Lulu. Krypto tries to save him, but due to a piece of Jarlsberg cheese inside a Batman toy he ate laced with green kryptonite, he loses his powers. Later, Krypto comes across the shelter pets who agree to help him, with Ace only agreeing after Krypto blackmails him.

Meanwhile, Lulu recruits a group of guinea pigs, captures the Justice League, and heads to Stryker's Island to free Luthor. The shelter pets try to stop her but fail miserably. They regroup in the Hall of Justice where Ace tells a distraught Krypto he used to be the puppy of a family with a toddler. One day, the toddler nearly fell down the stairs when Ace bit her arm and pulled her to safety. Upon seeing the bite-marks, the parents assumed Ace attacked her and sent him to the shelter. However, Ace stands by his actions and ideals. Encouraged, Krypto leads the pets to LexCorp. While there, a kitten named Whiskers, who can create weapons at will, attacks them, and the team traps her. At Stryker's Island, the shelter pets confront Lulu, but put themselves in prison cells when she threatens to harm Krypto. Lulu frees Luthor, who betrays her and locks her in his cell. She breaks out easily and decides to destroy the Justice League and Luthor herself.

The kryptonite passes through Krypto's system, restoring his powers. Fearing for their safety, he asks his friends to stay out of harm's way and heads to LexCorp. He defeats the guinea pigs while Lulu captures Luthor and launches a rocket from the building. This forces Krypto to choose between the Justice League or Lois, who is in a nearby helicopter. He decides to save Lois while his friends help the League. Enraged, Lulu puts the orange kryptonite in her brain, becoming a kaiju-sized version of herself. The Justice League and the pets team up to stop her. Realizing she has become too powerful, Krypto decides to use the "Solar Paw Punch", a move that can defeat any supervillain but will likely kill the user. The attack removes the kryptonite from Lulu's brain and her redeemed henchmen trap her in a hot dog stand.