The following version of this book was used to create the guide: Mellors, Coco. Cleopatra and Frankenstein. Bloomsbury, 2022.

Mellors' novel is divided into seventeen chapters that trace the eight-month relationship between Cleo and Frank, a young woman from London and a middle-aged man from New York, where the novel is set. Mellors begins the narrative with a witty and flirtatious conversation between these two characters on New Year's Eve. Through dialogue, readers learn that Cleo is an aspiring artist whose immigrant visa is about to expire. Frank is an establish man twenty years her senior, who owns a successful advertisement agency.

The next chapter jumps ahead six months in the narrative's timeline to Frank and Cleo's wedding. They are efficiently married at a courthouse, and afterwards they get their auras read by a psychic who informs them their colors do not align. Frank's friend hosts their extravagant reception, where Frank gets drunk and almost drops Cleo when they dance. Cleo ingests cocaine with her friend in the bathroom, and at the end of the night, Frank shoots off a firework that nearly hits his friend, Anders. Anders and Cleo slept together at the start of Cleo and Frank's relationship, unbeknownst to Frank.

Mellors then changes to the perspective of Quentin, Cleo's friend, as he breaks up with his boyfriend and attends an orgy. Quentin is lonely and fears that Cleo has abandoned him now that she spends all of her time with Frank. At the orgy, Quentin meets a man named Alex, who introduces him to methamphetamine. The next chapter enters Frank's perspective, who is hungover at work. Mellors reveals that Frank's mother was an emotionally abusive alcoholic, and Frank visits his college-aged sister, Zoe, in the hospital. Zoe suffered a seizure from drinking while on epilepsy medication. When Cleo arrives, she reminds Frank of his mother and he feels ashamed.

Unlike Frank, Zoe lacks money and cannot afford to keep partying. Shortly after her hospital stay, she attends a sex positivity class and admits she has never orgasmed before. After, she finds Cleo at a club, and is surprised when they experience a genuine bond. Zoe has never had true friends who care about her because women are often intimidated by her beauty. Zoe's sympathy for Cleo grows since she sees how lonely Cleo is. The next chapter explores Cleo's loneliness in greater depth through a conversation between Frank, Cleo, her father, and her stepmother. Cleo's father left her to start a new family after Cleo's mother died by suicide. Cleo no longer has a sense of belonging.

To uplift their spirits, Frank and Cleo take a delayed Honeymoon in France, but Frank ruins it by accepting a bet to jump from their hotel balcony into a swimming pool. Cleo leaves and goes dancing by herself in town, but she gets lost on her way back. When Frank finds her they are both relieved and reconcile. The next chapter switches to the perspective of Eleanor, who is a new worker at Frank’s agency. Frank and Eleanor grow close through comedic emails, and Mellors alludes to the beginning of an emotional affair.

Concerned by Cleo’s growing dissatisfaction, Frank buys Cleo a pet sugar glider to cheer her up. Though Cleo has quit painting and struggles with unhappiness, the pet distracts her. Frank promises to always take care of Cleo, but when she confronts him about his drinking one night, he lashes out in anger. An intoxicated Frank then accidently pees on the sugar glider in the toilet and drowns it. Frank then leaves for a business trip and Mellors switches to the perspective of Anders. He buys Cleo’s painting at a gallery and she comes over to thank him. They have sex and make future plans to stick together, but when Frank returns to New York, Anders worries about the commitment and chaos of the affair, and leaves Cleo. He considers taking a job in California.

Though Cleo desires to leave Frank, she ultimately stays in her marriage for stability. However, she begins to understand how unhealthy her relationships are and grows more depressed. Mellors draws Cleo’s suicidal ideation out over the span of a chapter, and by the end of it, Cleo swallows her wedding ring and cuts her wrist. Mellors hops to the perspective of Santiago, Frank’s friend, who visits Cleo in a psychiatric care hospital, since Frank is busy working. Cleo makes Santiago promise not to tell anyone about her situation, but when Santiago visits Anders in California, he tells him the news. Anders wants to rush back to New York, but Santiago stops him from hurting Cleo more.

Once Cleo is released from the hospital, she and Frank go to his cabin in upstate New York. The couple undergo a large fight that Mellors has built up throughout the novel, in which Cleo accuses Frank of being selfish and Frank treats Cleo like she is crazy. They agree their marriage is no longer sustainable. Mellors brings the narrative back to Zoe’s life. To secure more money, Zoe uses an escort service that pairs older men with college-aged women. She meets a kind man who wants someone to talk to, and he advises her to have a more positive perspective. Zoe finally achieves orgasm on her own.

The next chapter leaps ahead two months. Cleo and Frank are officially split up, and Cleo lives with her friend. They attend the party of an artist Cleo knows, and Cleo sees Anders there. She refuses to forgive him and hangs out with the artist instead, who encourages Cleo to try art again. The two of them start a riot by bashing his ice sculpture and Cleo nearly gets arrested, but she is invigorated by a new direction.

Mellors revisits Eleanor’s perspective and gives updates on the health of her father, who is bedridden. Once her father dies, Frank visits Eleanor and they reconnect. Frank and Eleanor finally strike up a romance and Eleanor convinces Frank to visit Cleo one more time for closure. Meanwhile, Cleo has moved to Italy for an artist residency. When Frank arrives, she tells him about Quentin, who is now addicted to meth and no longer a part of her life. She also shows him her paintings inspired by her suicide attempt. Frank serves her divorce papers, but in the end they express how important they are to each other, and how they want to remain close.