Gone Girl tells the story of Nick and Amy Dunne's difficult marriage, which is floundering for several reasons. The first half of the book is told in first person, alternately, by both Nick and Amy; Nick's perspective is from the present, and Amy's from the past by way of journal entries. The two stories are very different. Amy's account of their marriage makes her seem happier and easier to live with than Nick depicts. Nick's story, on the other hand, describes her as extremely anti-social and stubborn. Amy's depiction makes Nick seem more aggressive than he says he is in his story.
Nick loses his job as a journalist due to downsizing, and Amy loses her job as a magazine quiz writer shortly after. The couple relocate from New York City to his small hometown of North Carthage, Missouri, in part so the couple can help care for his dying mother. He opens a bar using the last of his wife's trust fund and runs it with his twin sister, Margo. The bar provides a decent living for the three Dunnes, but the marriage becomes more dysfunctional. Amy loved her life in New York and hates what she considers the soulless "McMansion" which she and Nick rent.
On their fifth wedding anniversary, Amy goes missing. Over time, Nick becomes a prime suspect in her disappearance for various reasons: he used her money to start a business, increased her life insurance, and seems unemotional, at times even smiling inappropriately, on camera and in the news. The police later find boxes of violent pornography and other items he had denied purchasing in the woodshed in Margo's garden, further implicating him. It is revealed that Amy was pregnant, and Nick hires Tanner Bolt, a lawyer who specializes in defending men accused of killing their wives.
In the novel's second half, the reader learns Amy and Nick are unreliable narrators and that the reader has not been given all of the information. Nick has been having an affair with one of his college students named Andie, and Amy is alive and hiding, trying to frame Nick for her "death". Her diary is revealed to be fake, intended to implicate Nick to the police. Nick soon discovers that Amy is framing him but has no way of proving it.
Together, Nick, Margo, and Tanner Bolt work to find ways to change the public's perception of Nick. Nick discovers the truth about two people who supposedly harmed Amy in the past: a former comedian named Tommy O'Hara and Hilary Handy, Amy's former classmate. According to their sides of the story, Amy had set Tommy up for seeing another woman, and Hilary for not doing things the way Amy wanted her to. Nick comes across an amateur reporter named Rebecca and allows her to interview him, and due to the positive reception, he's granted an interview with Sharon Schieber. There, he is apologetic and seemingly repentant of his affair with Andie, and appeals to Amy to come back.
Amy is robbed by fellow guests of a motel she was hiding in and is left without any money. Desperate, she seeks help from her obsessive first boyfriend, Desi. He agrees to hide her, but Amy soon feels trapped in his house as Desi becomes possessive. After seeing the TV interview with Sharon Schieber, she is convinced that Nick really does want her back. She murders Desi and returns to her husband, saying she had been kidnapped and imprisoned by her former boyfriend. Nick knows she is a killer, and that her pregnancy was never legitimate, but he stays in the marriage because he has no proof of her crimes and deceits. Amy forces him to fake his love, hoping that he will eventually love her the way she wants to be loved. She begins writing her memoirs, while Nick writes his own memoir exposing Amy's lies. Aware of his intentions to expose her, Amy then impregnates herself with Nick's semen from the fertility clinic, and makes him delete his book by implicitly threatening to keep him from their unborn child and turn it against Nick. In the end, Nick chooses to stay with Amy, keeping the charade forever, for his child's sake.