Oryx and Crake is the story of Snowman, a hermit living in a post-apocalyptic world ravaged by plague and overrun with genetically modified animals and plants. Snowman, or Jimmy, knew the creators of this strange world and worked alongside them. Crake, his brilliant but amoral friend, engineered the plague that reconfigured the world. Oryx, an object of desire to both men, is an enigmatic woman who helped to usher in Crake's new, peaceful world.
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 to search for supplies even though it is overrun by dangerous genetically engineered hybrid 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 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 an online trivia game called Extinctathon . Jimmy and Crake spend much of their leisure time online 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 very much love- struck by the gazing eyes of a young Asian girl seen in the porn.
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; peaceful, gentle, herbivorous humanoids who only have sexual intercourse 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 has other major and ultimately fatal effects. Crake officially hires Jimmy to help market it. At the Rejoov compound, Jimmy eventually sees a human in the Craker habitat and 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 for her and makes herself sexually available to him. As their relationship progresses, Jimmy becomes increasingly fearful that Crake has found out about it. 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, deliberately caused by it, breaks out and begins wiping out the human race and causing mass chaos outside of the protected Rejoov compound. Realizing that this was planned by Crake all along, and sensing that something dangerous is happening regarding Crake and Oryx, Jimmy grabs a gun 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 injured and silent Oryx, saying that he and Jimmy are immune to the virus. Jimmy lets them in, whereupon Crake looks directly into Jimmy's eyes and with the words "I'm counting on you," he slits Oryx's throat with his jackknife. Jimmy then immediately shoots Crake dead.
During Snowman's journey to scavenge supplies, he cuts his foot on a sliver of glass and becomes infected. He returns to the Crakers' camp and learns that three ragged true humans are camping nearby. Snowman follows the smoke to their fire and surreptitiously sees two dangerous looking 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.