After Flint Lockwood, Hubie, Marina, Rocko, Splatter, Petra, Beanie, Timmy, Pikatwo, Bonkers, Fawn and Buck along with Zazu and Maren and their other friends save the world from the food storm in the first film, super-inventor Chester V, the CEO of Live Corp, is tasked to clean the island. He relocates Flint, Hubie, their friends, and the citizens of Swallow Falls to San Franjose, California. Unbeknownst to our heroes, the FLDSMDFR survived the explosion and landed in the center of the island, and Chester is determined to find it. Chester invites Flint, his biggest fan, to work at Live Corp, where he meets Chester's assistant Barb, a talking orangutan with human intelligence. Six months later, Flint humiliates himself during a promotion ceremony when his invention, the "Celebrationator", explodes. Meanwhile, Chester is informed that his search-parties on the island have been attacked by monstrous cheeseburgers named Cheespiders (a combination of a Cheeseburger and a Spider) which are learning how to swim. Seemingly fearing the world's inevitable doom, Chester tasks Flint to find the FLDSMDFR and destroy it once and for all. Despite Chester's demands to keep the mission classified, Flint recruits his girlfriend, meteorologist Sam Sparks; her cameraman Manny; police officer Earl Devereaux; Steve, a monkey who communicates via a device on his chest; and "Chicken" Brent. Hubie, Marina and their friends are invited to help as well, but much to Flint's dismay, his father Tim joins the crew and they travel to Swallow Falls on his fishing boat. Maren is pleased, knowing she can use her boat.
Upon arriving back at Swallow Falls, they notice that a jungle-like environment made of food has overgrown the island. Tim stays behind with Maren, while Flint, Hubie and the others investigate, finding a vast habitat of living food animals called foodimals and meet a cute strawberry named Barry (named by Sam). Tim and M, searching for sardines at his abandoned tackle shop, along with Maren encounter a family of humanoid pickles and bond with them by fishing. Chester discovers that Flint allowed his friends to join him on the mission, so he travels to the island with Barb, chagrined and determined to separate them, and he arrives just in time to save them from a Cheespider. Flint then finds his old lab and invents a device to find the FLDSMDFR. After escaping a Tacodile attack, Sam and Marina notice that the foodimal was protecting its family, and they both suspect Chester is up to no good. Sam attempts to convince Flint to spare the foodimals, but Flint is intent on making Chester proud. Sam leaves in anger, and Flint's other companions go with her (including Steve). However as they leave, Hubie, Marina and their friends sneak off and follow Flint and Chester, knowing that something fishy is going on.
In the jungle, Manny confirms Sam's suspicions when he reverses the Live Corp logo to reveal the "Live" as "Evil" spelled backwards. In addition, Sam proves that the foodimals mean no harm by taming a Cheespider. They also learn that the foodimals had known the truth about Live Corp before. Upon realizing Chester's intentions and that Hubie and his friends have followed Flint, the group is then ambushed by Evil Corp employees.
Flint finds the FLDSMDFR, but notices a family of cute marshmallows and becomes hesitant to destroy the machine. Chester immediately seizes control of the FLDSMDFR and announces his plot to make his updated line of food bars out of the foodimals. A crushed Flint is knocked into the river. Hubie, Marina and the others watch in horror. They hurry to save him, only to lose Zazu who gets snatched away by three hyenas, Shenzi, Banzai and Ed. They had been secretly working for Chester the whole time. Hubie and Marina manage to find them moments later, but are too late when Zazu is shoved into a geyser (birdie boiler) and blasted off into the sky. Buck forces Hubie, Marina and Rocko into the river to save Flint while he and the others are surrounded and captured by Evil Corp.
While Maren is having coffee, Zazu collides into her boat. They see that Hubie, Marina and Rocko have managed to rescue Flint and they bring him to his father. After explaining the bad news, they and the foodimals all work together to allow Flint, Barry, Hubie and his friends to infiltrate the Evil Corp building that is under construction on the island. Flint frees the trapped foodimals and fight Chester's employees, along with the hyenas.
Afterwards, Flint, Hubie and his friends confronts Chester, who threatens to make food bars out of their friends. Chester makes numerous holograms of himself to overwhelm Flint, but Flint uses the Celebrationator to expose the real Chester, allowing Flint to rescue his and Hubie's friends. The hyenas arrive one again to attack our heroes, but are no match and they flee for their lives. Chester tries to make off with the FLDSMDFR, but is thwarted by Barb, who has a change of heart and Chester gets eaten by a Cheespider.
With the island safe from Chester V and Evil Corp destroyed, Flint returns the FLDSMDFR to its place and frees it from Chester's control and the foodimals continue to live in peace as more are born. The film ends with Flint fishing with his father for the first time, finding it enjoyable.
Not long after, Maren takes Hubie, Marina and their friends to their next destination. She and Zazu say goodbye to them and reassure that they will cross paths again in the future. After they leave, Hubie and his friends are left teary-eyed, but happy.
A scene after the credits is shown with Maren sailing the ocean with Zazu, knowing they can't wait to get home and tell Pooh and his friends of their adventures.