The story is told through a series of journal entries written by the story's protagonist, Charlie Gordon, a man with an IQ of 68 who works a menial job. He is selected to undergo an experimental surgical technique to increase his intelligence. The technique has already been successfully tested on Algernon, a laboratory mouse. The surgery on Charlie is also a success and his IQ triples.

Charlie falls in love with his former teacher, Miss Kinnian, but as his intelligence increases, he surpasses her intellectually and they become unable to relate to each other. Also, his new intelligence scares his co-workers at his job; they start a petition to have him fired and, when Charlie finds out about it, he quits. As Charlie's intelligence peaks, Algernon suddenly declines — losing his increased intelligence and dying shortly afterward. Charlie discovers that his intelligence increase is also only temporary. Unable to do anything to prevent the change, Charlie ultimately reverts to his original mental state in a swift reversal of his original growth. He tries to return to his original life and job but cannot stand everyone feeling sorry for him so he decides to move away. His last wish before he leaves is that someone put flowers on Algernon's grave.