The story begins with Crypto and Superman enjoying their usual heroic lives, but everything changes when Lex Luthor takes over the Justice League. Since the greatest superheroes of the world are no more, Crypto forms a new super team with pets from the shelter who receive superpowers. So he meets Ace, PB, Merton and Chip. Together they become the League of Super Pets and embark on a mission to save the Justice League from Lex Luthor.

As with most major animated films, the cast consists of several big Hollywood names. Dwayne Johnson plays the role of superdog Crypto, Superman's pet, voiced by John Krasinski. Other characters and actors include Kevin Hart as Batman's dog Ace the Bat Hound, Vanessa Bayer as Wonder Woman's size-changing pig, Natasha Lyonne as Flash's speedy turtle Merlon and Diego Luna as Green Lantern Chip's electric squirrel.