In the jungle of Nool, Horton (voice of JIM CARREY) is a likable elephant who enjoys hanging out with his friends, including Morton (voice of SETH ROGEN), Tommy (voice of JONAH HILL) and little Katie (voice of JOEY KING). One day while frolicking in the river, Horton thinks he hears a voice coming from a little speck that floats by him in the air.
While no one believes his claim -- especially the mother Kangaroo (voice of CAROL BURNETT) who doesn't want the elephant stirring up any sort of make-believe commotion among the kids -- Horton takes it upon himself to protect the speck. With it landing on a piece of clover, the elephant tries his hardest to communicate with whatever or whoever might be on it.
Little does he realize the latter is more accurate as the speck is really a world that contains a town -- Whoville -- comprised of various Whos. They're blissfully unaware that they're so small in such a big world, and are planning on celebrating their centennial. The only doubter is Mayor O'Malley (voice of STEVE CARELL) who, with wife Sally (voice of AMY POEHLER), is a parent to 97 kids, all of them girls except for JoJo (voice of JESSE McCARTNEY) who keeps to himself and never speaks.
The Mayor realizes something odd is happening to their world, but the Chairman (voice of Dan Fogler) and the rest of the council don't believe him, and certainly don't want him rocking the boat. Yet, when he finally makes contact with Horton, he knows he isn't crazy. The same holds true for the elephant, although the fact that he's the only one who can hear the Whos means that the Kangaroo will do anything to quiet him, including hiring hit-eagle Vlad (voice of WILL ARNETT) to get and dispose of the piece of clover and the speck on it.
From that point on, Horton and the Mayor do what they can to get the rest to believe them, all as others try to put them in their place, actions that will ultimately threaten all of Whoville.