The novel focuses on a character called "Snowman", living in a post-apocalyptic world near a small group of primitive and innocent human-like creatures whom he calls Crakers. Flashbacks reveal that Snowman was once a boy named Jimmy who grew up in a world dominated by multinational corporations that built privileged walled compounds to isolate and protect their employees and the employees' families from a degenerating outside society. The companies had operated by developing and marketing advanced technology products such as medical treatments and genetically engineered hybrid animals, but now no other humans are evident, and the compounds have become decaying ruins.
Near starvation, Snowman decides to return to the ruins of a compound named RejoovenEsense to search for supplies, even though his excursion risks encountering dangers including feral populations of the hybridized animals. He concocts an explanation for the Crakers, who regard him as a teacher, and begins his foraging expedition.
In Snowman's recollection of past events, Jimmy's family moves to the HelthWyzer compound, where his father works as a genetic engineer. Jimmy meets and befriends a brilliant science student named Glenn. Jimmy begins to refer to him as Crake when he uses that name in an online trivia game called Extinctathon. Jimmy and Crake spend much of their leisure time playing online games, smoking "skunkweed", and watching underground videos such as live executions, graphic surgery, Noodie News, frog squashing, and child pornography.[4][5][6] During one of their child pornography viewings, Jimmy is very much lovestruck and horrified by the gazing eyes of a young girl seen in the porn known as Hott Tott.
After graduating from high school, Crake attends the highly respected Watson–Crick Institute, where he studies advanced bioengineering, but Jimmy ends up at the loathed Martha Graham Academy, where students study humanities, only valued for their propaganda applications. Jimmy gets a job writing ad copy, while Crake becomes a bioengineer at RejoovenEsense. Crake uses his prominent position to create the Crakers, peaceful, gentle, herbivorous humanoids, who have sexual intercourse only during limited polyandrous breeding seasons. His stated purpose for the Crakers, actually a deliberate deception, is to create "floor models" of all the possible options a family could choose in the genetic manipulation of their future children. Crake's bio-engineering team consists of the most expert players gathered from the online Extinctathon community.
Crake tells Jimmy about another very important project, a Viagra-like super-pill called BlyssPluss, which also promises health and happiness, but secretly causes sterilization in order to address overpopulation. Crake officially hires Jimmy to help market it. At the Rejoov compound, Jimmy notices a human in the Craker habitat and thinks he recognizes her as the girl from the pornographic video. Seemingly unaware of Jimmy's obsession with her, Crake explains that her name is Oryx and that he has hired her as a teacher for the Crakers. Oryx notices Jimmy's feelings for her and makes herself sexually available to him, despite also being Crake's romantic partner. As their relationship progresses, Jimmy becomes increasingly fearful that Crake has found out about it or has known all along. He also makes a promise to both Oryx and Crake that he will look after the Crakers if anything happens to them.
After Crake's wonder drug BlyssPluss is widely distributed, a global pandemic breaks out and begins wiping out the human race and causing mass chaos outside of the protected Rejoov compound. Realizing that the pandemic had been deliberately introduced by Crake and was distributed by including it within BlyssPluss, and sensing further immediate danger, Jimmy grabs a gun and goes to confront Crake, who is returning with Oryx from outside the compound and needs Jimmy to let them in. Crake presents himself to Jimmy with his arm around an unconscious Oryx, saying that he and Jimmy are immune to the virus. Jimmy lets them in, whereupon Crake slits Oryx's throat with a knife. Jimmy then immediately shoots Crake dead.
During Snowman's journey to scavenge supplies, he encounters aggressive hybrid animals and retreats into the RejoovenEsense compound. He finds some indications that other humans have survived – seeing smoke on the horizon near the compound and briefly hearing voices on radio receivers in the compound. He carelessly breaks a scavenged bourbon bottle after binge drinking its content, and cuts his foot on a sliver of the glass. The cut becomes infected. His treatment of the wound with the medications he can find has some initial success, but the infection later gets worse again. He returns to the Crakers' camp and learns that three other humans have recently encountered the Crakers and are camping nearby. Snowman follows the smoke to where they are gathered around a campfire. Snowman is unsure of what to do, and considers killing them. Whether he kills them, introduces himself or quietly flees, and whatever happens afterwards, is left open to question at the end of the book.
