Oryx and Crake is narrated by Snowman, who started life as Jimmy. Snowman describes a world in which mankind has largely been destroyed by a laboratory-produced virus.  Genetically modified creatures – pigoons and wolvogs – roam the deserted landscape.  He is one of the few human survivors, loosely responsible for watching over the Children of Crake – a tribe of genetically modified people created by his one-time best friend.

Snowman recalls his childhood in flashbacks, living in restricted Compounds as the son of two scientists working for OrganInc Laboratories. As he remembers the past, he journeys to one of the abandoned Compounds to scavenge for a weapon and supplies.

In memory, his mother suffers a breakdown, and later runs away from the Compound. She liberates Jimmy's pet rakunk (a raccoon-skunk modified animal), and joins a group rebelling against the work of the Corporations.

Jimmy becomes acquainted with the highly intelligent Glenn, nicknamed Crake. The boys spend their free time smoking "skunkweed", browsing a host of disturbing internet sites and playing computer games such as Extinctathon. On one occasion the boys find a film of a child prosititute who fascinates Jimmy.

The boys' different aptitudes take them to separate universities: Crake attends the prestigious Watson Crick for scientifically-minded students; Jimmy ends up at the run-down Martha Graham.

After college, Crake wins a prize job with a leading biotechnology corporation, where he begins work on a project to create a race of genetically modified people, known by Jimmy as the Crakers. Jimmy works as an advertising copywriter until Crake offers him a job.

Crake locates the child prositute from the internet film, now grown up, and hires her to teach the Crakers about their artificially pristine environment.  He names her Oryx. Both Jimmy and Crake fall in love with Oryx, but it is Crake who wins her. When Jimmy and Oryx later become sexually involved, they keep the relationship secret from Crake.

Unknown to Jimmy, Crake develops a pandemic virus which is distributed around the world in seemingly harmless products. When the virus is activated, the results are catastrophic, wiping out most of humanity.  Jimmy survives, having been innoculated by Crake. Oryx dies at the hands of Crake, who has discovered her affair with Jimmy. Jimmy kills Crake, leaving him alone with the innocent, other-worldly Crakers.

As Snowman, Jimmy leads the Crakers to the coast where they live in relative safety. He invents a creation myth for them, with Crake as a powerful god and Oryx as the protector of nature.

Snowman returns from his quest for supplies to hear reports from the Crakers of other human survivors nearby. The story closes as Snowman contemplates whether or not to approach the survivors.