Narrated by an unnamed third-person limited-omniscient narrator, The Heart Goes Last opens with Stan and Charmaine, a young married couple, sleeping in their third-hand Honda. A financial catastrophe has hit the Rust Belt region of the United States. Gangs roam the streets and make it unsafe for people like Stan and Charmaine, who have lost their middle-class jobs and been forced to abandon their debt-laden homes.
While working at a seedy bar, Charmaine sees a TV ad for the Consilience/Positron project, a walled community purporting to end unemployment and crime. Charmaine is drawn to the idea of safety and stability, and Stan goes along with her to the interview. After spending a night in a luxurious hotel, Charmaine is sold on the project; they sign away their freedom and join, agreeing that they can never leave.
In Consilience/Positron, they live one month in a house provided to them within the walled community and the next month in the prison of Positron. They are given jobs inside and outside the prison that fit their skill set. Stan tends to chickens inside the prison and repairs the scooters that participants use to get around Consilience. Charmaine is Chief Medications Administrator, tasked with euthanizing undesirable members of the community.
Stan and Charmaine enjoy the normalcy of the life at first, but after several months, Charmaine starts an affair with the man who lives in their home when she and Stan are in prison. They meet on switchover days in different deserted homes. Charmaine becomes a different person with Max. She tells him that her name is Jasmine and, as Jasmine, she fulfills her fantasies as a sexual submissive. Stan finds a note from Jasmine to Max under their fridge and becomes obsessed with Jasmine. He believes Jasmine is the woman who lives in their home when he is serving his month in prison.
As a scooter repair person, Stan plants a secondhand mobile phone in his wife's scooter seat; he tracks the movements of "Jasmine," planning to ambush her on a switchover day. However, as he goes to confront "Jasmine," he finds a woman named Jocelyn: she is a member of the Surveillance team with Consilience. She controls the cameras within the city and knows that her husband Phil—known to Charmaine as Max—has been having an affair with Charmaine. Jocelyn corrupts the identity coding system to make it so Stan stays with her in the house instead of taking his turn in prison. She also manipulates the system to keep Charmaine in prison for several months.
Jocelyn makes Stan watch the surveillance tapes showing Charmaine and Phil together. She then makes Stan reenact the affair with her. Stan begrudgingly goes along with her perverse role-playing, knowing Jocelyn has all the power over him. Meanwhile, Charmaine stays in prison and worries about Max and Stan not knowing what has happened to her. On Valentine's Day, Jocelyn reveals that she has been using Stan and Charmaine as part of a plan to bring down Ed, her cofounder on the Consilience/Positron project. She believed the project would help people who were hit by the financial collapse, but it has become a way for rich investors to profit from exploitation. She explains that Ed has started selling organs belonging to the people Charmaine euthanizes. With the criminals gone, they are now pulling people off the streets outside the city or people within the city who try to escape or cause trouble. Jocelyn says that she made her husband Phil seduce Charmaine, and then recreated the affair so there would be footage of her having sex with Stan, inventing a motive for Charmaine to want to have Stan killed.
Jocelyn orchestrates it so that Charmaine has to euthanize Stan so that any higher-up watching footage of the procedure will believe he is really dead. In reality, Jocelyn has filled the needle with a sedative, and Stan wakes up in a storage warehouse. Jocelyn gives him a flash drive full of damning evidence about what Ed has been doing; Stan must get it out to a journalist who can break the story.
Charmaine passes out after doing the injection and wakes up back in her house. She is told by Jocelyn and an accomplice named Aurora that she will have to play the role of grieving widow, as Stan's funeral is coming up soon. Stan, meanwhile, assumes a new identity code as Waldo, and works in the Possibilibots division of the company. Budge, a colleague of Stan's in cahoots with Jocelyn, ships Stan to Las Vegas dressed as an Elvis Possibilibot. He travels with Veronica, a former sex worker who used to be friends with Charmaine. Stan learns of another evil venture: Positron has developed a process to erase a person’s memory and have them imprint on the first person they see when they wake up. A rich person can choose anyone they want and they will be kidnapped and taken to surgery. When the person wakes up, the client will have what is essentially a brain-washed sex slave. This process was used on Veronica, but a nurse gave Veronica a blue teddy bear to comfort her. When she woke up, the first thing she saw was the bear, and she became obsessed with it. The process cannot be reversed.
While grieving Stan's death, Charmaine becomes the target of Ed's affection. Jocelyn encourages her to stay close to him and spy on him, revealing that Stan isn't dead. Charmaine goes along with it, but learns that Ed has made a Possibilibot in her image and plans to bring her to Las Vegas to have her memory wiped and make her his sex slave. On the flight there, Jocelyn drugs Charmaine, seemingly breaking a promise to keep her safe.
Upon arrival in Las Vegas, Stan is sheltered by a group of Elvis impersonators, one of whom sends him on an escort date with Lucinda Quant, a TV journalist who he gives the flash drive to. Stan links up with his criminal brother, Conor, who has been working with Jocelyn for a while. Conor brings Stan to the clinic where Ed plans to erase Charmaine's memory. They are there when an ambulance arrives with Charmaine, Ed, Jocelyn, Aurora, and Phil. Jocelyn tries to make up for manipulating Charmaine and Stan by giving Charmaine the surgery to become obsessed with Stan. She also erases Phil's memory to set him up with Aurora. Meanwhile, Lucinda Quant breaks the story. To get rid of Ed and avoid the spotlight landing on herself, Jocelyn makes Ed become obsessed with Lucinda Quant, who plans to take him to a country where he can't be extradited; she will live out her last years with a man who can fulfill her sexual fantasies.
On the first year after their renewal of vows, Stan and Charmaine live happily in a house in Las Vegas with their three-month-old daughter, Winnie. Jocelyn visits to tell Charmaine that she never received the surgery and thus her new devotion to Stan has come from a genuine desire. Charmaine is upset to learn this, as it leaves open the possibility of being seduced by a man like Max again. Jocelyn suggests that it is better to do something because she chooses to, not because she's forced to.
