The novel is made up of a series of progress reports written by a man named Charlie Gordon. As the novel begins, Charlie Gordon is mentally disabled, with an IQ of 68. He works at a bakery and attends classes at night to learn how to read and write. Because of Charlie’s motivation, his teacher, Alice Kinnian, recommends him for a cutting-edge experimental surgery designed by Professor Harold Nemur and Doctor Strauss. Strauss and Nemur believe that they can greatly increase intelligence through this operation. They’ve already performed their surgery on a mouse named Algernon, who has become super-intelligent. Charlie competes with Algernon in mazes and other intelligence tests, and loses every time.
Charlie undergoes the surgery, and is told that soon he’ll have an IQ of 185. At first, Charlie doesn’t feel intelligent at all. He continues working at the bakery, where his coworkers tease him and bully him for his clumsiness. In the evenings, Charlie continues meeting with Alice, who tells him to remain patient. Charlie begins to have vague flashbacks to his childhood—a period of time that he barely remembers.
At work, Charlie slowly shows signs of increased intelligence. He becomes adept at mixing dough, and gets a raise for his efforts. He has wet dreams, which Dr. Strauss—who acts as his therapist—explains to him. Charlie also beats Algernon in intelligence tests. At the same time, he begins to have more frequent flashbacks: he remembers that his mother, Rose Gordon, would spank him for being bad, and that she vehemently denied that he was mentally challenged. He also had a sister named Norma Gordon, who hated Charlie for getting too much attention from their parents.
Alice teaches Charlie grammar and encourages him to read, and Charlie quickly becomes more and more intelligent. He begins to alienate his coworkers, who resent him for being smarter than they are. Charlie also notices that Alice is very pretty, and he tries to pluck up the courage to ask her out.
Charlie confronts an ethical dilemma when he discovers that his coworker Gimpy, who’s always been gruff but kind to him, is stealing from the bakery. Charlie asks Professor Nemur for advice, but Nemur says that it’s an unimportant issue. Alice urges Charlie to resolve the dilemma by exploring his own values and beliefs, and Charlie is able to convince Gimpy to stop stealing anymore.
Encouraged by his discussions with Alice, Charlie asks Alice on a date. The date goes well, and Charlie decides that he’s in love. Alice tells Charlie that he’s being too hasty, however: although he’s very intelligent now, he still has the emotional intelligence of a child. Alice and Charlie go on other dates, and Charlie slowly realizes that he’s vastly more intelligent than Alice.
Charlie is fired from his job at the bakery—his coworkers, furious with his new intelligence, sign a petition asking for his immediate dismissal. Charlie is hurt. The only coworker who doesn’t sign the petition, Fanny Birden, says goodbye to Charlie, and warns him that it was a sin for Adam and Eve to eat from the Tree of Knowledge. Angry and upset, Charlie goes to Alice’s apartment, where he tries and fails to be physically intimate with her.
Charlie continues to work closely with Professor Nemur. He flies out to Chicago for a medical conference, where Nemur’s discovery is supposed to be one of the highlights. At the conference, Charlie begins to resent Nemur’s condescending attitude—although Charlie is now far more intelligent than Nemur, Nemur continues to regard him as a “guinea pig.” Charlie embarrasses Nemur in front of his colleagues, and frees Algernon from his cage. Together, Charlie and Algernon leave Chicago, with Charlie resolving to live life on his own terms from now on.
Back in New York, Charlie finds an apartment for himself. He meets women late at night and attempts to have sex with them, but he frightens them away. His fortunes improve after he meets his apartment neighbor, a strong, energetic woman named Fay Lillman. Fay is uninhibited, and tells Charlie that she’d like to have sex with him. Meanwhile, Charlie remembers an episode from his childhood in which his sister Norma became furious with him. Norma wanted to have a dog, but their father, Matt Gordon, refused to give her one unless she let Charlie play with it. Charlie has another vivid flashback of his mother spanking him after he accidentally embarrassed a girl at his school. Charlie visits his father, who now works in a barbershop in the Bronx. Matt doesn’t recognize Charlie, and Charlie is unable to force himself to reveal his identity.
Charlie decides to devote himself to studying neuroscience—in this way, he believes, he can help other mentally disabled people. At the same time, he launches a turbulent relationship with Fay. At first, Charlie can’t have sex with Fay without experiencing traumatizing hallucinations in which he sees a younger version of himself—the “old Charlie.” Over time, however, Charlie learns to be confortable around Fay.
Charlie is then horrified to discover that Algernon’s intelligence is vanishing—suggesting that the same might happen to him soon. Charlie reunites with Professor Nemur and begs for funding to research the issue. Nemur arranges for Charlie to pursue this research. In the meantime, Charlie visits the Warren State Home for the mentally ill—the home where Charlie might have to live if his hypothesis is proven correct and he loses his intelligence. Warren State is surprisingly pleasant, although Charlie is still terrified at returning to a state of mental disability.
Charlie gets drunk and confronts Nemur and Strauss. Charlie tells them they’re condescending and conceited, but comes to realize that he’s become just as bad. Shortly after this confrontation, Charlie makes a breakthrough in his research: he concludes that Nemur’s brain surgery will always be impermanent. In the long run, Charlie’s own intelligence will disappear, and he’ll become mentally disabled again. Algernon dies and Charlie buries his body and decorates the grave with flowers.
Charlie tries to tie up loose ends before his loses his intelligence. He goes to visit his sister Norma, who still cares for their mother. Charlie’s mother now suffers from dementia—while she recognizes Charlie, she seems to forget who he is from time to time. Norma, on the other hand, is a kind, bright woman, who’s happy to reunite with Charlie. She tells Charlie that she’s hated herself for years because of the way she treated him. Charlie is so moved by his conversation with Norma that he has to leave. He decides to forgive his mother for her cruelty—there’s simply no point in hating her.
Charlie’s intelligence fades quickly. He becomes irritable, and Fay breaks off all ties with him. Alice continues to visit Charlie, although she’s upset by his moodiness. One night, Charlie and Alice have sex, and Charlie feels that he’s experiencing “something different”—a love few people find in a whole lifetime.
Charlie loses all his intelligence and enters a state of mental disability once again. He returns to the bakery, and succeeds in getting his old job back. His coworkers, who formerly bullied him, now treat him with more respect. Nevertheless, Charlie decides that he can no longer be around his coworkers or Alice—he can’t stand to talk to people who remember a time when he was a genius. He decides to go to the Warren State Home. In his final progress report, Charlie says goodbye to Alice, Professor Nemur, Doctor Strauss, and everyone else he’s met since the experiment. In a postscript, he asks “someone” to put more flowers on Algernon’s grave.