The story is written in the first-person perspective of Christopher John Francis Boone, a 15-year-old autistic boy living in Swindon, Wiltshire. Although Christopher's condition within the autism spectrum is not stated explicitly within the novel, the summary on the book's inside cover describes it as Asperger syndrome.
Ed, his father, discovers the book and confiscates it from Christopher, after a brief fight between them. In his search for the hidden book, Christopher uncovers a trove of letters to himself from his mother, dated after she allegedly died — which his father had also concealed. Christopher had been told by Ed that she died of a heart attack, Christopher assumes it's an aneurysm, but judging from the letters, Christopher concludes that she is still alive and that his father has lied to him. He is so thoroughly shocked by this fact that he is unable to move, curls up on the bed, vomits, and groans for several hours until his father returns home.
Ed realises that Christopher has read the letters and cleans him up. He then confesses that he had indeed lied about Judy's death and also that it was he who killed Wellington, stating that it was a mistake due to his anger after a heated argument with Mrs Shears.
Christopher, having lost all trust in his father and fearing that he may also try to kill him since he had already killed Wellington, decides to escape from home and live with his mother. Guided by his mother's address from the letters, he embarks on an adventurous trip to London, where his mother lives with Mr Shears.
After a long and confusing journey, evading policemen who have been dispatched to find him (after Ed called the police about his disappearance), and feeling ill because of the overwhelming information from the crowds and the signs in the trains, he finally finds his way to his mother and Mr Shears' home, and waits outside until they arrive.
His mother, Judy, is happy at his arrival and tries to keep him with her; she cannot believe that Ed would tell Christopher that she was dead. His mother decides to let Christopher stay with her and Mr Shears in their small London apartment. Mr Shears doesn't want Christopher living with them and never did. Moreover, very soon after arriving, Christopher wants to return to Swindon in order to take his mathematics A-level. His mother eventually leaves Mr Shears, their relationship having apparently broken down because of the conflict over Christopher.
She then moves into a rented room in Swindon and, after an argument with Ed, agrees to let Ed meet with Christopher daily for a little while. However, at this stage, Christopher remains terrified of his father; he hopes Ed will be imprisoned for killing Wellington. The story ends with Ed getting Christopher a pet dog, because Toby, Christopher's pet rat, had died, and promising that he will rebuild trust with Christopher slowly, "no matter how long it takes," in his daily, brief sessions. Christopher asserts that he will take further A-level exams and attend university. He completes his first mathematics A-level with top grades and — despite previously wanting to be an astronaut — his ultimate goal is to become a scientist.
The book closes with Christopher optimistic about his future — since he successfully solved the incident of the murdered dog, went to London on his own, found his mother, and got an A in his A-level maths exam.
Christopher has many traits that separate him from others because of his perception of life. He is unable to recognise and comprehend facial expressions besides 'happy' and 'sad' and has difficulty in understanding metaphors and jokes. He likes lists and facts, has a fear of strangers and new places, and his favourite dream is one in which all "normal" people (those who are unlike him) die. In addition to that, he is over-sensitive to information and stimuli. For this reason, he screams and reacts violently to people who touch him. However, he doesn't mind pressing his fingers against those of his parents as a gesture of love. He curls up and groans to protect himself against overwhelming noise or information.
Christopher hates the colours yellow and brown, but adores red. This extends to adding red food dye to brown- or yellow-coloured food (and being unable to eat two different kinds of food that are touching), and also his belief that seeing three, four or five red cars in a row means it's a "good", "quite good", or "super good" day, respectively, while four yellow cars signify a "black" day, on which he will not eat his lunch or talk to anyone. Finally, he dislikes eating food from new places and the furniture being moved.
Christopher's mathematical interests are reflected in his numbering his chapters strictly with prime numbers, ignoring composite numbers such as 4 and 6. So the first is Chapter 2, followed by 3, then 5, 7, 11, and so on. In addition, the contents in consecutive chapters alternate: Chapter 2 is about the unfolding story; Chapter 3 explores some aspects of the narrator's inner life not necessarily directly relevant to the immediate action; Chapter 5 returns to the narrative. This alternation continues throughout the book with the story often digressing into seemingly unconnected subjects such as Christopher's atheism and the Cottingley Fairies.
Another technique used to emphasise the perceptions experienced by people with autism is the switching of fonts and use of long, run-on sentences when describing the surroundings. The book's overall structure, as well as its content, supports the literary device that what we are reading is a novel penned by an autistic person. The book's narration does not use any exaggeration or hyperbole to describe the plot: the style of language, based on Christopher's point of view, is literal fact. This technique of fictional autobiography was exploited by Daniel Defoe in what is regarded as the first novel in English, Robinson Crusoe, although it really follows a more Sherlock Holmes-style structure.
Christopher's narration is precise and reliable about objective facts but his view of the story's events is often very different from what might be expected. For example, in one scene, Christopher is nearly killed by an oncoming train as he retrieves his pet rat, who has scampered on to the tracks of the London Underground. Through his narration, the scene unfolds completely, but he remains unaware of the danger he is in, and of the closeness of his brush with death. This is also an example of dramatic irony, in which the reader understands more about a situation than the character does. Christopher also represents (what would not necessarily be obvious to readers) the fact that not every child will think in the same way — another element that the book has been praised for. Nonetheless, some readers on the autism spectrum have criticised it for giving an inaccurate portrayal of their identity.