The book tells the story of Horton the Elephant, who, while splashing in a pool, hears a small speck of dust talking to him. Horton surmises that a small person lives on the speck and places it on a clover, vowing to protect it. He later discovers that the speck is actually a tiny planet, home to a community called Whoville, where microscopic creatures called Whos live. The Mayor of Whoville asks Horton to protect them from harm, which Horton happily agrees to, proclaiming throughout the book that "a person’s a person, no matter how small."

Throughout the book, Horton is trying to convince the Jungle of Nool that "A person is a person no matter how small" and that everyone should be treated equally. In his mission to protect the speck, Horton is ridiculed and harassed by the other animals in the jungle for believing in something they can't see or hear. He is first criticized by the sour kangaroo and her joey. The splash they make as they jump into the pool almost reaches the speck, so Horton decides to find somewhere safer for it. But the news of his odd new behavior spreads quickly, and he is soon harassed by the Wickersham Brothers, a group of monkeys. They steal the clover from him and give it to Vlad Vladikoff, a black-bottomed eagle. Vlad flies the clover a long distance, with Horton in pursuit, until Vlad drops it into the middle of a field of clovers that stretches for hundreds of miles.