In the Jungle of Nool, a caring, imaginative elephant named Horton (Jim Carrey), the jungle's nature teacher, takes a dip in the pool. A dust speck floats past him in the air, and he hears a tiny yelp coming from it. Believing that an entire family of microscopic creatures are living on that speck, he places it on top of a clover that he holds in his trunk. In fact, he finds out the speck harbors the city of Whoville and all its inhabitants, led by Mayor Ned McDodd (Steve Carell). He has a loving wife, Sally (Amy Poehler), 96 daughters (all voiced by Selena Gomez), and one son named JoJo (Jesse McCartney), who, by Who custom, is next in line for the mayoral position, and as such, gives it his best effort to give JoJo enough attention. Unaware to Ned, JoJo doesn't understand his father's wish. Ned is aware, though, that JoJo doesn't speak and tries to befriend him to get him to speak.
The Mayor finds out from Dr. Larue that Whoville will be destroyed if Horton doesn't find a "safer more stable home." So Horton resolves to place the speck atop Mt. Nool, the safest place in the jungle. This outlook earns Horton nothing but ridicule from the inhabitants of Nool, especially from the strict official of the jungle, the Sour Kangaroo (Carol Burnett), who tries to get Horton to give up the speck, so as not to put ridiculous ideas into the heads of the children. Ever faithful to his motto, "A person's a person, no matter how small," Horton refuses. Also taking force toward Horton are the Wickersham brothers (all voiced by Dan Fogler), a group of bullying monkeys who love making misery.
All the small incidents that Horton experiences on his trek across the jungle have a catastrophic effect on Whoville. He almost falls off a rickety bridge, which causes a dentist's needle to accidentally slip into the Mayor's arm while getting a root canal taken care of. At night, leaving the clover outside will cause it to frost, which creates winter in the summer down in Whoville. As the other Whos become suspicious, the Mayor finally reveals the truth, but at first, the Whos don't believe him any more than the animals believe Horton.
In the meantime, the Kangaroo has enlisted a nefarious "black-bottomed eagle" named Vlad Vladikoff (Will Arnett) to get rid of the speck by force. Vlad manages to steal the speck and drop it from hundreds of feet into a valley full of identical clovers. The impact nearly demolishes Whoville like an earthquake, yet Horton finds the right clover, after painstakingly picking 2,999,999 clovers through the field. The earthquake is enough to convince the rest of the Whos that the mayor is not crazy, and they all tell Horton they believe in him.
Kangaroo finds out that Horton still has the speck, and, as her patience completely runs out, forms a mob by telling lies to get rid of the speck once and for all. The animals plan to rope and cage Horton, but Kangaroo turns this into a chance for attention, and offers Horton an ultimatum: give up the speck and "admit" he was wrong, or pay the price. Despite a heartfelt speech from Horton that clearly touches the animals, Kangaroo still takes this refusal as an insult, orders them to proceed with the torture, and drop the speck into a pot of boiling beezlenut oil, which is shown to have acidic properties.
The Mayor enlists all of his people to make noise by shouting, "We are here!", so the animals can hear them. JoJo runs off to Whoville's abandoned Star-Studying Tower and soon Ned takes off after him. Inside, he reveals his ingenious invention: the Symphonyphone, a giant machine that serves as an orchestra, and proceeds to add it to the mix of sounds. Still, the sound isn't loud enough. The animals don't hear anything and Kangaroo, who has now caged Horton, takes the clover with a chuckle, holds it over the oil, and lets go. In a last-ditch effort to be heard, JoJo grabs the horn used to project Horton's voice, runs up the highest tower and yells "YOPP!" A sound wave emerges and ripples up to the clouds, which are already under a lot of stress from the other sounds, and collides with them, causing an explosion.
Hearing the Whos' cries, Rudy (Josh Flitter), the Kangaroo's son, grabs the clover and returns it to Horton, refusing his mother's orders to return to her pouch. The animals finally realize the atrocity they almost committed. The Kangaroo is humiliated and ashamed, but Horton forgives her, and offers his friendship, to which the Kangaroo accepts. At the end of the film, everyone helps Horton carry the speck up to the top of Mt. Nool. After a big number of the cast singing REO Speedwagon's "Can't Fight This Feeling", the camera zooms out, revealing that along with numerous other worlds in our universe, the jungle of Nool is just one speck among numerous others like our planet.
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