Charlie Gordon is a young man with an IQ of 68 who has a job at a box factory and attends night classes in an effort to improve himself. A (very fictional) experimental brain operation becomes available that promises to triple intelligence (it has already done so for a mouse named Algernon), and Charlie excitedly decides that he wants to give it a try. The story consists solely of Charlie's diary entries from the time he hears about the operation through the operation and his dramatic increase, and subsequent decrease, of IQ.

Charlie's increased intelligence opens up to him the understanding of everyday things that had been beyond his grasp, and at his peak he soars to the level of genius, ironically identifying the flaw in the scientific work of the two scientists who developed the operation he has undergone, and thus destroying their careers as their shallow research destroys the life that had been his.

Among the everyday things Charlie understands for the first time is the fact that two of his male co-workers have regularly taken advantage of his retarded state to make fun of him, sometimes roughly. Charlie also becomes self-conscious more generally, which makes it impossible for him to stay in the place where he has been so degraded, even after his formerly misbehaving pals become sympathetic.

At the end of the story he has fallen back to his original level of intelligence--and may continue to decline, if we take the suggestion from the fate of his fellow subject, Algernon, who rises, falls, and then dies. Charlie has only a dim memory of having done something important. His self-esteem is strong, however, and he decides to leave his familiar world and find a place where people won't know about his embarrassment.