The story is written in two different viewpoints, that of Nick Dunn and his wife, Amy Elliot Dunn. Nick's story begins on the morning of his fifth anniversary. He is unhappy with his marriage and frustrated with his life in general. After being let go from his job — writing for a magazine in New York City — he returned to his hometown of Carthage, Missouri, with his wife, Amy, to help his twin sister take care of their dying mother.
Since that time, his mother has died, his father has been put in a nursing home, and Nick has used the last of his wife's trust fund to open a bar. On the morning of his anniversary, Nick gets to the bar late. After reminiscing about his wife's yearly scavenger hunt to celebrate the day, Nick receives a phone call from a neighbor, telling him the front door to his house is open.
When Nick returns home, he discovers his wife is gone, a teakettle whistles in the kitchen, and the living room looks as if there's been a struggle. Nick calls the police. Detectives Rhonda Boney and Jim Gilpin arrive. Nick cooperates with them, giving DNA samples and a vague alibi for his whereabouts that morning. As he assures the police that his wife has no enemies and is near perfection, internally, he thinks about her as a controlling and manipulative woman, so completely different from the one he married.
Interspersed with Nick's telling of the present story is Amy's diary, which recalls their past. She talks of falling in love with Nick when she first saw him at a party in New York. They share an instant connection, but don't see each other for another eight months. They accidentally meet on the street. Amy goes on to tell of their marital bliss, sex life and how he's helped her overcome the obsessive dominance of her psychologist parents, Rand and Marybeth Elliot, authors of a series of books, the "Amazing Amy" series. The books, popular years earlier and loosely based on Amy Elliot's own life, narrate the trials and successes of the character Amy and her friends. Then Amy describes how tolerant she is of Nick's life away from her. She refuses to turn him into a "dancing monkey," available to her every beck and call.
The day after Amy's disappearance, her parents arrive to help in the search. The police arrange a press conference. Unfortunately, Nick suffers from a hangover and stares woodenly into the cameras as Amy's father breaks down in tears. The tenseness of the moment elicits Nick's trigger response, he smiles. It makes him look unfeeling.
As the day progresses, Nick is allowed to open the first clue to Amy's annual anniversary treasure hunt. It leads him to his office at the college where he teaches part time. Another clue is found. Amy's notes seem to be filled with positive accolades for her husband, which makes Nick secretly wonder what's going on, as Amy had nothing but negative things to say to him lately. Detective Gilpin also finds a pair of ladies underwear hanging from the AC unit. Nick says they're Amy's. They sometimes role-play student/teacher affairs in his office, just to spice up their love life.
Amy's diary entries tell of how Nick was laid-off from his job. Amy claims he sunk into a bitter, alcohol-infused depression. He also bought a lot of luxury items on credit that he never used, stacking them up in a spare room.
Amy also lost her job. Although saddened at the prospect of being unemployed, they didn't have to worry about money as Amy had a hefty trust fund. Her parents, however, soon asked if they could borrow most of it as they made some terrible business deals. With little money left, and no job prospects, Nick jumps at the chance to return home to Carthage where to help his twin sister, Margo (Go), help care for their dying mother. Nick grows more distant and volatile after the move. Amy admits to feeling like a nonperson. She thinks she could disappear, and he wouldn't care.
A command post is set up at a local hotel to coordinate the volunteers who have come to help search for Amy. One man, a childhood friend of Nick's, claims the police aren't looking in the right places. The Blue Book Boys, a collection of men laid off from a plant the year before, now roam the town in angry mobs. Most of them live in an abandoned mall. Detective Boney assures Nick that all leads are being followed. One of the volunteers, Shawna, comes on to Nick, under the guise of trying to be empathetic. She insists on taking a selfie with him. Nick, again, smiles woodenly. The following day, Nick secretly takes a trip to Hannibal, Missouri, as he's figured out Amy's next anniversary clue. He finds another note in which she spouts wonderful things about him. That night he and several other men visit the abandoned mall to try and talk to some of the Blue Book Boys. After a series of antagonistic encounters, they finally find a man who recognizes Amy's picture. He claims Amy came to the mall on Valentine's Day, hoping to find someone who'd sell her a gun because she was scared.
The police aren't impressed with Nick's detective work. They ask if he might consent to another interview with them. In the afternoon, Nick follows the next clue to his father's old house. The security code has been changed, and he sets off the alarm. He finds the next clue, but has no idea of the answer. He returns to his sister Go's house. After she goes to bed, Nick receives a message on a disposable cell phone that he carries. He's been ignoring calls on it for several days, but this time, he opens the text.
His girlfriend is waiting outside Go's house. Her name is Andie, and she insists on coming inside. Nick tries to convince her of the danger their relationship puts him in, but Andie needs to know he still loves her. They fall asleep in the living room. Go sees Andie in the morning and is furious. Although she never liked Amy, she can't believe Nick is an adulterer. She thinks he needs to hire a lawyer.
That afternoon, a cable news show anchored by Ellen Abbott, a former prosecutor, takes up Amy's case. Ellen is biased against Nick and plasters the pictures of him and his wooden smile across the airwaves. She even interviews Shawna, whom Nick had spurned at the volunteer center. Shawna says that Nick flirted with her and seemed very calm during the search. Nick, in an effort to get out of town and do something useful, treks to St. Louis to talk to Amy's former boyfriend, Desi. He attempted suicide in Amy's dorm room when she broke up with him. Desi says he hasn't spoken to Amy in years but that he occasionally writes her letters. He still seems obsessed with her, but assures Nick he had nothing to do with her disappearance.
Meanwhile the police begin to hound Nick, searching for evidence that he killed Amy. They find several odd Internet searches and a bunch of credit card bills that Nick insists aren't his. During a candlelight vigil, a woman claiming to be Amy's best friend announces that Amy was pregnant and demands to know what Nick did with her. Nick tells Go that he and Amy tried to get pregnant, even freezing his sperm, but that she gave up on the idea.
Amy's diary entries tell of the continuing disintegration of her marriage. Nick is distant and cold, using her for sexual pleasure, but not love. When she talks about having a baby, he tells her he can't handle any more stress in his life or he will crack. Four months later, two weeks before she disappears, she discovers she is pregnant. She tells her only friend Noelle the news. She wonders whether Nick will be happy and jokes that if she ends up dead, it was probably him.
Nick hires Tanner Bolt, a high-priced celebrity attorney. Nick also figures out Amy's last scavenger hunt clue. It leads him to the storage room in Go's yard. Inside, he finds thousands of dollars' worth of merchandise. It's the stuff the police say someone bought using his credit card. Nick knows Amy must be alive and has set him up to punish him.
In the next section of the book, it's no longer Amy's diary entries, but her perspective that tells how she's planned her disappearance and murder for a full year. She admits the Diary Amy is a work of fiction, something she's worked on to point the finger at Nick. She describes seeing Nick and Andie together and how it sparked her desire for revenge.
Amy hides in a cabin in the Ozarks, paying with $10,000 in cash that she's squirreled away for the event. She wants to live long enough to see Nick tried for her murder. Then she'll go on a cruise and kill herself. She's dyed her hair and gained weight so people won't recognize her. She describes how she faked friendships, pregnancy and abuse.
A couple at the cabins where she is staying steals Amy's money, forcing her to come up with another plan. She contacts her old flame, Desi. She tells him she escaped from Nick because of his abuse. Desi keeps her hidden at his lake house and treats her like a queen.
Nick discovers that others in Amy's past have suffered similar acts of revenge. She framed a former boyfriend for rape and made her best friend appear insane. The cops hound Nick, believing he's Amy's killer. Andie confesses to being his mistress on national television. Nick begins to alter his defense so that he comes across as a man who believes his wife is alive, hiding from him because he's been such a jerk. He sends Amy coded messages in his interviews, basically begging her forgiveness, admitting his guilt and demonstrating his willingness to treat her like the brilliant woman she is. The police arrest Nick for Amy's murder.
Amy believes Nick to be repentant and ready to treat her as she desires. But Desi refuses to let her leave his lake house. He keeps her as his prisoner while trying to convince her it's for her own good. Amy conceives of another drastic plan to escape. She abuses herself with a wine bottle and ties herself with twine for a few days to simulate the effects of being a sexual prisoner. Then she has sex with him, drugs him and lays out evidence that he's been keeping her tied up in the house. Finally, she brutally stabs Desi and returns to Nick.
The final sections of the book deal with Nick, Go and Detective Boney trying to find the evidence to prove that Amy set up her own abduction and murdered Desi. But Amy is a brilliant psychopath and has covered all the evidence in place to prove her story. She confesses the truth to Nick, but she will never admit it to anyone else. Nick thinks he's outplayed her when he writes an account of the whole sordid incident, but she plays her trump card. She has impregnated herself with sperm saved from when they went through fertility treatments. If he does not back her story and continue to live with her as a doting husband and father, she will destroy his life again by claiming he abused their child. In the end, the two set up a kind of fake life together. The last line of the novel, however, indicates that Amy is not happy with how Nick is playing the game, leaving the reader to wonder if she will contrive some new horror to try and control him.