The book tells the story of Horton the Elephant who, in the afternoon of May 15 while splashing in a pool located in the Jungle of Nool, hears a small speck of dust talking to him. Horton discovers that the speck of dust is actually a tiny planet, home to a microscopic community called Whoville, where the Whos reside. The Whos are led by a character known as the Mayor.
The Mayor asks Horton (who, though he cannot see them, is able to hear them quite well, because of his large ears) to protect them from harm, which Horton happily agrees to do, proclaiming throughout the book that "even though you can’t see or hear them at all, a person’s a person, no matter how small." In doing so he is ridiculed and forced into a cage by the other animals in the jungle for believing in something that they are unable to see or hear. His chief tormentors are Vlad Vladikoff, the Wickersham Brothers and the Sour Kangaroo. Horton tells the Whos that, lest they end up being boiled in "Beezelnut Oil", they need to make themselves heard to the other animals. The Whos finally accomplish this by ensuring that all members of their society play their part in creating lots of noise so they are heard by the jungle folks. In the end it is a "very small shirker named JoJo" whose final addition to the volume creates enough lift for the jungle to hear the sound, thus reinforcing the moral of the story: "a person’s a person, no matter how small."
Now convinced of the Whos’ existence, Horton’s neighbors vow to help him protect the tiny community.