A speck of dust is dislodged from a flower and sent floating through the Jungle of Nool. While bathing in the pool, Horton the elephant, who is also the jungle's eccentric nature teacher, hears what seems to be a tiny yelp as the speck passes by. He assumes that a society of microscopic creatures lives on the speck and finally manages to catch it to rest on a clover.
Horton's assumption is proven correct, as the speck is actually the city of Whoville, led by Mayor Ned McDodd, who has a wife Sally, ninety-six daughters, and one son named Jojo, who is the eldest child and next in line to be mayor. Jojo, however, does not want the position, but does not say anything out of fear of disappointing his father. Because Horton is now carrying the speck around on the clover, Whoville soon begins to experience strange phenomena, such as earthquakes and changes in the weather. The Mayor attempts to caution Whoville on the situation, but is challenged by the Town Council, led by the opportunistic yet condescending Chairman.
The Mayor eventually makes contact with Horton via horn stuck up a broken water pipe and learns from Dr. Mary Lou LaRue that if Whoville does not find a "safer, more stable home", then their world will be destroyed. Horton resolves to take the clover to the top of Mt. Nool, as it is the safest place in the jungle. Jane Kangaroo, who is the head of the jungle, is in disbelief of Horton's claims and tries several times to make him give up the clover, which he refuses. Also taking force against Horton are the Wickersham Brothers, a group of monkeys who love to make misery. The Kangaroo is eventually fed up with Horton's refusal to co-operate and enlist a vulture named Vlad Vladikoff to forcibly remove the speck.
Horton's best friend, Morton the mouse, warns him of Vlad, who then pursues him through the jungle. After a long chase, Vlad finally manages to steal the clover and drops it into a massive field of identical clovers, causing an apocalyptic tremor in Whoville. Horton spend hours looking through the clovers, finally managing to find the right one (the 3,000,000th clover). Through Mrs. Quilligan the bird, the Kangaroo learns that Horton still possesses the speck and rallies the other animals into turning against Horton, claiming that his actions will lead to anarchy.
As he nears Mt. Nool, Horton is cornered by the other animals, but is offered the chance to escape punishment by renouncing Whoville's existence. He refuses and proceeds to give a moving speech, but the Kangaroo orders the other animals to rope and cage him, and to have the speck and the Whos destroyed in a pot of boiling beezlenut oil. The Mayor enlists all of the inhabitants to make noise by playing various instruments and shouting "We are here!" so the animals may hear them, assisted by Jojo's "Symphonophone" an invention which creates a huge musical contribution (revealing that his true passion is music), but it still is not strong enough to break the sound barrier. As Horton lies beaten and captured, the Kangroo takes the clover and drops it. But just before it hits the oil, Jojo grabs the horn from the pipe and runs up the highest tower, and yells "YOPP!", breaking through the sound barrier. The Kangaroo's son, Rudy, grabs the clover and returns it to Horton. Finall hearing the Whos and realizing that Horton was telling the truth, the animals isolate the Kangaroo for turning them against their friend. Horton is praised by his neighbors for his integrity and even forgives the Kangaroo, who befriends him with a makeshift umbrella for the Whovile. And finally, the animals and Whos come together in song and recite the chorus from "I Can't Fight This Feeling". The film ends with the narrator revealing that the Jungle of Nool, or rather Earth, is just one speck, like Whoville, among numerous others, floating in outer space.
- Jim Carrey as Horton the Elephant
- Steve Carell as Mayor Ned McDodd
- Carol Burnett as Jane Kangaroo
- Will Arnett as Vad Vladikoff
- Seth Rogen as Morton the Mouse
- Dab Fogler as the Chairman of Whoville and Yummo Wickersham
- Isla Fisher as Dr. Mary Lou LaRue
- Jonah Hill as Tommy
- Amy Poehler as Sally O'Malley
- Jaime Pressly as Mrs. Quilligan
- Charles Osgood as the Narrator
- Jesse McCartney as JoJo
- Josh Flitter as Rudy Kangaroo
- Niecy Nash as Mrs. Yelp
- Laura Ortiz as Jessica Quilligan
- Selena Gomez as Helga
- Joey King as Katie
- Bill Farmer as Willie
- Heather Goldenhersh as a Who Girl