Following the events of the first film, inventor Flint Lockwood and his friends celebrate their success in saving the world from the food storm created by the “Flint Lockwood Diatonic Super Mutating Dynamic Food Replicator” (FLDSMDFR). Chester V., the CEO of Live Corp and Flint’s childhood idol, offers his company’s services to help clean up the mess left by the storm. He hires Flint, but during his short tenure at Live Corp, Flint enters a competition for a promotion only to humiliate himself during a presentation.
Chester shows Flint that the FLDSMDFR is still functioning and creating food-animal hybrids (foodimals), one of which attacked his employees stationed on Swallow Falls. Chester tells Flint that he needs to travel alone to the island, find the FLDSMDFR, and insert a USB with a kill code to stop it. However, Flint gathers a team: his girlfriend Sam Sparks; her cameraman Manny; police officer Earl; Steve, Flint’s pet monkey; and reformed bully “Chicken” Brent McHale. Flint also grudgingly accepts the help of Tim, his widowed father, who takes them to the island using his fishing boat. When Chester learns that Flint is not alone, he and his much-abused orangutan assistant Barb gather some Live Corp employees and follow.
While Tim stays on the boat, making friends with some living pickles and teaching them to fish, Flint and his friends work their way through the jungle-like environment that now completely covers Swallow Falls. They encounter more foodimals, such as sushisheep,shrimp chimpanzees, taco crocodile, watermelon elephant, and a living strawberry they name “Barry”. A giant cheeseburger spider chases Flint and the gang, but Chester arrives, scaring it off and joining in the mission. Sam becomes suspicious of Chester’s motives, as his claims that the foodimals are dangerous do not align with what they have observed already, and the others start to agree. Flint is too afraid of failure to listen, eventually leading to Sam and the gang striking out on their own. They meet up with and befriend the cheespider, realizing she only hurts people wearing Live Corp gear. When Manny deduces that the foodimals have realized “live” is merely meant to be an anagram of “evil”, a Live Corp security team ambushes and takes them captive.
Flint, Barb, and Chester finally track down the FLDSMDFR, but after meeting and befriending some living marshmallows it created, Flint defies Chester and refuses to use the kill code. Chester knocks Flint into a river, where he is rescued by the marshmallows and reunites with Tim. Chester uses the device, which actually is a hacking device, to reprogram and steal the machine. The Lockwoods realize that, without the FLDSMDFR, the existing foodimals will die out. As Flint offers his condolences, he is surprised to discover that the foodimals, having watched old footage of Flint inventing the FLDSMDFR, have dubbed him “Nwoo”(pronounced En woo) the creator, and revere him. Inspired, Flint vows to get his machine and his friends back.
Tim and the foodimals help Flint and Barry sneak into the Live Corp base, where some captive foodimals are freed by Barry and proceed to drive away the Live Corp employees. When cornered, Chester threatens to put Flint’s friends in his food bar machine, which is also the fate he had designed for all foodimals and the reason he wanted to find the FLDSMDFR in the first place. He fires Barb when she objects to the violence, but Flint is able to overpower him with his inventions and frees his friends. Chester attempts to escape with the FLDSMDFR but Barb, having had enough with Chester’s cruelty towards her, steals it back and he is eaten by the Cheespider. Flint returns the FLDSMDFR to where he found it and restores it to normal. Flint reconciles with Sam, the gang and Tim, who let him try out fishing for the first time. It is shown during the closing credits that the residents of Swallow Falls have returned to their proper homes, adapting to the altered ecosystem and happily continuing their lives. The FLDSMDFR still continues foodimal production, and they live peacefully alongside the humans.
In a mid credits scene, Barb develops a crush on Steve, attempting to ask him on a date.