The novel focuses on a post-apocalyptic character named Snowman, living near a group of primitive 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 and privileged compounds for the families of their employees. Near starvation, Snowman decides to return to the ruins of a compound named RejoovenEsence even though it is overrun by dangerous genetically engineered hybrid animals to search for supplies. 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 genographer. Jimmy meets and befriends a brilliant science student named Glenn. Jimmy begins to refer to him as Crake, when he uses that name in a trivia game called Extinctathon. Jimmy and Crake spend much of their leisure time playing games, smoking "skunkweed" and watching underground videos such as live executions, graphic surgery, Noodie News, frog squashing and child pornography. During one of their child pornography viewings, Jimmy is struck by the eyes of a young Asian girl.
After 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 RejoovenEsence. Crake uses his prominent position to create the Crakers, herbivorous humans who only have sexual intercourse during limited polyandrous breeding seasons. His stated goal is to create "floor models" of all the possible options a family could choose in the genetic manipulation of their future children. Crake's team consists of proficient players from the Extinctathon community.
Crake tells Jimmy about another project, a prophylactic agent, and hires Jimmy to help market it. At the Rejoov compound, Jimmy sees a human in the Craker habitat and immediately recognizes her as the girl from the pornographic video. Unaware of Jimmy's obsession with her, Crake explains that her name is Oryx and that he has hired her as a prostitute for himself and a teacher for the Crakers. Oryx notices Jimmy's feelings and makes herself available to him. As their relationship progresses, Jimmy becomes increasingly fearful that Crake has found out about it. He 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 is widely distributed, a global pandemic breaks out and begins wiping out the human race. Realizing that this was planned all along, Jimmy grabs a gun to confront Crake. Crake presents himself to Jimmy with his arm around Oryx, saying that they are the only three people immune to the virus. With the words "I'm counting on you," Crake slits Oryx's throat before being shot.
During Snowman's journey to scavenge supplies, he cuts his foot on a sliver of glass and becomes infected by some descendant of transgenic experiments. Hoping that the uniquely adapted Crakers can heal him, he returns to their camp and learns that three ragged true humans are camping nearby. Snowman follows the smoke to their fire and sees two men and a woman. Unsure of whether to befriend them or shoot them, Snowman checks his broken watch, thinks "Time to go" and makes up his mind.