The Accidental Tourist opens with Macon and Sarah Leary driving back home to Baltimore in the rain after a vacation at the beach. When Macon refuses to stop the car, Sarah suddenly announces that she wants a divorce. She accuses Macon of being incapable of comforting her, especially after the tragic murder of their 12-year-old son, Ethan. Macon is surprised. The book then flashes forward to after the couple has separated. Macon tries to adjust to the change, finding it strange to live in their family house all alone. In a somewhat compulsive way, Macon comes up with various "systems" of organization in order to manage the household chores. These habits are highly strange, such as washing the clothes in the bathtub while he showers. Macon, overcome by a grief he won't directly acknowledge, also struggles to keep a normal sleeping and eating routine.
Meanwhile, Macon tries to maintain a regular work schedule. His job is writing travel guides aimed at businessmen who are reluctant to leave their hometown. It is an ironic role for Macon, as he hates traveling and leaving his comfort zone in any way. Macon soon has to leave for a trip to England. Right before his departure, Sarah calls him to ask if she can come by and get her rug. They reveal to each other that they have both been struggling since the separation. On the way to the airport, Macon drops off his dog, Edward, at a kennel, where he strikes up a conversation with a young receptionist named Muriel Pritchett. In England, Macon has difficulty getting his work assignments done and itches to go home. When he returns to Baltimore, he picks up Edward and Muriel Pritchett tells him the dog was well-behaved, subtly flirting with Macon and giving him her business card. Macon can only think about Sarah, and he feels her absence as he walks back into his house with Edward.
Weeks go by and Macon is challenged by completing his England travel book. His boss, Julian, starts to call him, inquiring on his progress, and Macon promises he will have it done in a few weeks. Instead of working, Macon focuses his energy on his household systems, devising ones to ensure that he almost never has to leave the house to do grocery shopping. Despite being invited over for meals by his neighbors, who now know about his separation, Macon declines the gesture, feeling that he can trust no one. Much of his time is spent daydreaming about his former life and what went wrong in his marriage to Sarah. One night, when Macon walks down into his basement, he falls and breaks his leg. He ends up having to stay at his family house, with his sister Rose and his brothers Charles and Porter, while he recovers. We learn more about the Leary siblings and their shared tendency for strange organizational habits. We also learn about their childhood, and how the children were left to live with their grandparents by their volatile mother, Alicia.
Edward the dog increasingly starts acting out, eventually biting Julian when he visits Macon at the family house one day. Macon realizes he must do something about it and remembers Muriel Pritchett's business card. He calls her and they make an appointment to train Edward. At their meeting, Muriel is very forward and reveals many personal details about herself. Macon does not know how to interact with her, continually trying to bring the conversation back to training Edward. They continue with training lessons over the next few days. One night, Macon has a sexual dream about Muriel; the next day, when he sees her for the lesson, he abruptly kisses her and then instantly apologizes for it.
By October, Macon has finally made progress on his travel guide and goes to hand it in at Julian's office. Julian has slowly been hinting at his interest in Macon's sister, Rose, and requests to be invited over for dinner one night. He also asks Macon if he can start working on another U.S. guidebook.
As it turns into winter, Macon is able to remove his cast. Despite his recovery, he is continuing to stay at his family home rather than return to his old house. He takes off to New York City for a work assignment. While there, he goes to review a restaurant on the top of a very tall skyscraper. There, he has an anxiety attack—not only from the height, but also from the feeling of being very small and far away from everyone he loves. He calls his brother Charles for help and discovers that Edward has cornered Charles in the pantry. He has to call Muriel from the top of the building and ask her to go to his house to tame Edward.
The dog lessons continue and Edward shows improvement. Muriel increasingly shows her interest in Macon, which Macon tries to deflect. Muriel invites Macon to come to dinner with her and her 7-year-old son, Alexander, which Macon is unsure about, feeling that he is not ready to start another relationship. He drives to Muriel's house the night before the proposed dinner and tells her about the death of Ethan and his mixed feelings. Muriel comforts him and they end up sleeping together.
Macon starts to spend more and more time with Muriel, staying over at her house and becoming a surrogate father for the sickly Alexander. He enjoys settling into this new routine and the strange and foreign atmosphere of Muriel's working-class neighborhood. At the same time, he begins to notice more of Muriel's quirks that annoy him, such as her relentless talking and superficial interests. Macon's siblings start to become concerned that he is spending so much time away from them, wondering whether this new relationship is good for him. Macon finds out from Julian that he plans on proposing to Rose on Christmas.
Muriel and Macon's relationship progresses, with him meeting her parents and ingraining himself into her life more and more until he is practically spending all his time with her. Macon brings Muriel as his date to his sister Rose's wedding. There, he realizes the similarity between the flakiness of his mother, Alicia, and Muriel's own flightiness. Sarah is also at the wedding, and Macon is curious to learn if she has been dating anyone else. His concern with this makes him recognize his lingering feelings for his ex-wife.
In the following months, Muriel starts to pressure Macon to show more commitment to her. She requests to marry him in June, to which Macon replies that he's not ready, wanting to keep things more casual. She also begs to accompany him on his business trip to France, but Macon declines. Muriel suspects that Macon wants to leave her to go back to Sarah. Their two different attitudes to the relationship lead to the relationship's rupture, with Macon going back to live in his old house with Sarah. Macon and Sarah try to resume their former relationship, going on errands and seeing their friends together, but something has clearly changed between them.
When Macon is departing on his flight to Paris, he is startled to discover that Muriel is on the same plane. She has found out his travel information and has booked the same tickets, desperate to renew her connection with him. Macon allows her to follow him around to some degree in Paris, although he has committed to Sarah. One night, he hurts his back and is resigned to bed, unable to complete his assignments. Sarah shows up in Macon's hotel to take care of him while he is bedridden. She, of course, discovers Muriel's presence, and Macon must make a final choice between the two women. Considering how he has never been able to make his own choices in life, feeling always overwhelmed by the chaos of life around him, Macon chooses to leave behind the past and be with Muriel.
