The short story and the novel share many similar plot points, but the novel expands significantly on Charlie's developing emotional state as well as his intelligence, his memories of childhood, and the relationship with his family and Miss Kinnian.
The story is told through a series of journal entries written by the story's protagonist, Charlie Gordon, a man with a low IQ of 68 who works a menial job as a janitor in a plastic manufacture warehouse. He is selected to undergo an experimental surgical technique to increase his intelligence. The technique had 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. He also realizes that his co-workers at the factory, whom he thought were his friends, only liked him to be around so that they could make fun of him. His new intelligence scares his co-workers, and they start a petition to have him fired, but when Charlie finds out about the petition, he quits. As Charlie's intelligence peaks, Algernon's suddenly declines—he loses his increased intelligence and mental age, and dies shortly afterward, to be buried in a cheese box in the backyard of the lab where Charlie was tested. Charlie discovers that his intelligence increase is also only temporary. He starts to experiment to find out the cause of the flaw in the experiment, which he calls the "Algernon-Gordon Effect". Just when he finishes his experiments, his intelligence begins to regress to its state prior to the operation. Charlie is aware of, and pained by what is happening to him as he loses his knowledge and his ability to read and write. He tries to get his old job as a janitor back, and tries to revert to normal, but he cannot stand the pity from his co-workers, landlady, and Ms. Kinnian. Charlie states he plans to "go away" from New York and move to a new place. His last wish is that someone put flowers on Algernon's grave.
The novel opens with an epigraph discouraging people from laughing at those who are perplexed or weak of vision. The epigraph is taken from Plato's The Republic, part of which reads:
Any one who has common sense will remember that the bewilderments of the eye are of two kinds, and arise from two causes, either from coming out of the light or from going into the light, which is true of the mind's eye, quite as much as of the bodily eye.—Plato, The Republic
Charlie Gordon, 37 years of age, suffers from phenylketonuria and has an IQ of 68. He holds a menial job at a bakery which his uncle had secured for him so that Charlie would not have to be sent to a state institution. Wanting to improve himself, Charlie attends reading and writing classes at the Beekman College Center for Retarded Adults; his teacher is Alice Kinnian, a young, attractive woman. Two researchers at Beekman, Prof. Nemur and Dr. Strauss, are looking for a human test subject on whom to try a new surgical technique intended to increase intelligence. They have already performed the surgery on a mouse named Algernon, dramatically improving his mental performance. Based on Alice's recommendation and his own peerless motivation to improve, Charlie is chosen over smarter pupils to undergo the procedure.
The operation is a success, and within the next three months Charlie's IQ reaches an astonishing 185. However, as his intelligence, education, and understanding of the world around him increase, his relationships with people deteriorate. His co-workers at the bakery, who used to amuse themselves at his expense, are now scared and resentful of his increased intelligence and persuade his boss to fire him. One night at a cocktail party, a drunken Charlie angrily confronts his scientific mentors about their condescending attitude toward him, particularly Nemur because Charlie believed that more than anyone Nemur considered him as nothing more than another laboratory subject and not fully human before the surgical operation. Charlie also embarks on a troubled romance with Alice. Unable to become intimate with the object of his affection, Charlie later starts a purely sexual relationship with Fay Lillman, a vivacious and promiscuous artist in the neighboring apartment.
When not drinking at night, Charlie spends intense weeks continuing his mentors' research on his own and writing reports which include observations of Algernon, whom he keeps at his apartment. Charlie's research discovers a flaw in the theory behind Nemur's and Strauss's intelligence-enhancing procedure, one that could eventually cause him to revert to his original mental state. His conclusions prove true when Algernon starts behaving erratically, loses his own enhanced intelligence, and dies.
Charlie tries to mend the long-broken relationships with his parents but without success. He remembered that as a boy his mother had insisted on his institutionalization, overruling his father's wish to keep him in the household. Charlie returns after many years to his family's Brooklyn home, and finds his mother now suffers from dementia and, although she recognizes him, is mentally confused. Charlie's father, who had broken off contact with the family many years before, does not recognize him when visited at his worksite, a barbershop. Charlie is only able to reconnect with his now-friendly younger sister, Norma, who had hated him for his mental disability when they were growing up, and who is now caring for their mother in their newly-depressed neighborhood. When Norma asks Charlie to stay with his family, he refuses, but promises to send her money.
As Charlie regresses intellectually, Fay becomes scared by the change and stops talking to him. However, Charlie finally attains sufficient emotional maturity to have a brief but fulfilling relationship with Alice, who cohabits with him until the extent of his mental deterioration causes him to finally order her to leave. Despite regressing to his former self, he still remembers that he was once a genius. He cannot bear to have his friends and co-workers feel sorry for him. Consequently, he decides to go away to live at the State-sponsored Warren Home School, where nobody knows about the operation. In a final postscript to his writings, ostensibly addressed to Alice Kinnian, he requests that she put some flowers on Algernon's grave in Charlie's former backyard.