During the summer after their fifth grade year, Arnold and his best friend Gerald plan to make a humanitarian video to win a trip to San Lorenzo, where Arnold's parents were last seen. They try to record themselves making a home out of junk for one of their friends, eccentric Monkeyman, but it backfires, leaving Arnold heartbroken.Helga, who secretly has a longtime crush on Arnold, uses various footage she's compiled over the years showing Arnold's good deeds, and everyone in town surprises Arnold with the video. Arnold's teacher Mr. Simmons reveals to everyone that Arnold's video won the competition and he, his classmates of P.S. 118, and Helga's older sister, Olga fly to San Lorenzo.While on the plane, Arnold's pet pig Abner stows away in his backpack. When everyone arrives in San Lorenzo, they are greeted by Arnold's parents' old friend, Eduardo. Aboard a ship, Eduardo privately warns Arnold of the jungle's dangers and gives him an amulet said to lead them to the "Green-Eyed People", the residents of San Lorenzo's lost city. Later that night, Helga tries to confess her feelings to Arnold, but the boat is attacked by pirates. After learning the secret that Arnold kept from them, Gerald and the others shun him.When the group reaches a base camp, "Eduardo" reveals himself to be a mercenary named Lasombra, who disguised himself as Eduardo to deceive Arnold and the others. He and his men imprison everyone, explaining that the contest was a trick to lure Arnold to San Lorenzo so he could use him to find the lost city and its treasures. Helga and Gerald manage to escape and free Arnold, and use Arnold's father's old journal to find the city; unbeknownst to them, Lasombra anticipated this and placed a tracking device on Arnold's green eyed necklace. Arnold and his friends manage to evade the lost city's traps, while Lasombra pursues them, sacrificing most of his men to the traps.Meanwhile, Abner escapes and makes it back to Arnold's grandparents, Grandpa Phil and Grandma Gertie, who see this as a sign that Arnold is in trouble. The two meet with Helga's parents Big Bob and Miriam at the airport, who had received an SOS message from Helga's intelligent best friend, Phoebe. The group flies a rental plane to San Lorenzo, where they help the other kids defeat Lasombra's gang.Arnold and the others reach the city, finding it populated by children due to a "sleeping sickness" that has left its adult population comatose for nine years. The group finds a statue said to contain the Corazón, a treasure that may lead to a cure for the sickness. Lasombra corners them, taking Arnold hostage and stealing the statue. While Gerald and Helga give chase, Lasombra forces Arnold to open the statue using the amulet. When Lasombra tries to take the Corazón within, the statue's defense system shoots him in the forehead with a poisoned dart, sending Lasombra over a cliff.A mysterious man arrives and reveals himself to be the real Eduardo, who explains that the pirate "attacking" them earlier was him trying to rescue the group from Lasombra. Lasombra climbs back up from the cliff and gets into a brief scuffle with Eduardo, knocking the Corazón off the cliff, before succumbing to the poison and plummeting to his death. The group returns to the city, and Arnold finally sees his parents, Miles and Stella, who have also contracted the sleeping sickness. Without the Corazón to release the cure to the infected population, Helga uses her locket containing a photo of Arnold as a replacement. The temple releases the cure and the infected are revived. Arnold and the city's children reunite with their parents. Arnold thanks Helga for her loyalty and finally realizes the depths of her feelings for him, and the two share a kiss.A few months later, life as normal has resumed at Arnold's grandparents' boarding house, though now with Miles and Stella living there as well. Arnold says goodbye to his parents as he heads off for his first day of sixth grade with Gerald, Phoebe, and Helga. Gerald and Phoebe are seen holding hands walking to school together, while Arnold and Helga are also implied to be a couple despite Helga pretending to remain hostile towards Arnold at once in public. Arnold's parents walk with him and his friends to school and Arnold promises his mom and dad that they'll see him at 3:30 as the doors close behind him.