Oryx and Crake is told through the vantage point of a man named Snowman. Snowman is living in an outdoor setting near a body of water with a group of seemingly alien entities called Crakers. The Crakers ask him many questions and bring him one fish each week. Snowman exhibits a great deal of anger towards a man named Crake. In contrast, he is very fond of, and still hears the ephemeral voice of Oryx.
It is soon learned that Snowman used to be named Jimmy. Through his recounting of his past, the reader learns that he used to live on a compound belonging to a company called OrganInc. His father was a geneticist that worked with pigs used for human organ harvesting with a lab technician named Ramona. These animals, called pigoons, were the source of some tension in the marriage of Jimmy's parents. Jimmy's mother, Sharon takes issue with the level of genetic splicing taking place. Unlike her husband, she sees the animals as more than an amalgamation of proteins. Young Jimmy feels sad for the pigoons because they cannot do anything in their cramped quarters.
Jimmy's father was always critical of Jimmy's lack of skills in the sciences. He felt that Jimmy was ill equipped for success. It is revealed that Snowman recalls these things to pass his time, as there is nothing else to do. The sight of a rakunk reminds him of his pet rakunk Killer. Killer had been a birthday gift from Jimmy's father years ago.
Jimmy's mother, highly dissatisfied with her life in the Compound, runs away. She takes Killer with her. Jimmy misses both his mother and his rakunk but is not sure which one he misses more. Because of his mother's illegal departure, Jimmy is repeatedly questioned by the CorpSeCorps, the government’s security and investigative agency.
Jimmy met Crake/Glenn a few months before his mother's departure. As such, the two things are tied together in his mind. Jimmy and Crake begin to spend a lot of time together after school. During this time, they play online games, i.e. Extinctathon, and view many vulgar websites for entertainment purposes. One game in particular, Extinctathon, gives them their nicknames. The game requires vast knowledge of all of the extinct species on Earth. Crake (Glenn) and Jimmy (Thickney) take on nicknames as part of the game. Crake's nickname sticks whereas Jimmy's does not. It is also during these numerous web-surfing hours that they first see Oryx. About eight years old, Oryx was on a child pornography website. Crake prints out her image and gives Jimmy a copy.
After high school, Jimmy and Crake attend different institutions. Jimmy goes to the run-down Martha Graham Academy, a school that concentrates on the much-undervalued arts. He attends this school because his grades in the sciences were too poor to gain him access to any other school. In addition, Jimmy prefers words to numbers. Crake, on the other hand, gains admission to the Watson-Crick Institute thanks to his superior grades. While in college the two drift apart a bit. Jimmy goes to visit Crake during a holiday and marvels at the facilities available at the Watson-Crick Institute.
Once Jimmy graduates from high school, he gets a job at AnooYoo, a company that markets and creates beauty and age-defying products. Jimmy is responsible for their ad campaign. While working at AnooYoo Jimmy has many sexual flings. After several years of working for the company, the CorpSeCorps come to show Jimmy a video and ask him about the whereabouts of his mother. In the video, Jimmy witnesses his mother's execution. Jimmy falls into a depression after watching the video.
Crake saves Jimmy from his deep sadness. Crake offers Jimmy a job at his company. Jimmy is now charged with creating the ad campaign for the BlyssPluss Pill, a medicine that promises to revert aging. Crake shows Jimmy the other part of his project, Paradice. Crake has created a humanoid creature that embodies many of the best qualities of humans and various animals from around the world. In particular, Crake wishes to create an immortal species. He removes many of the "undesirable" human traits from his creation. The Paradice models, or Crakers as they are later called, live in an enclosure inside of the compound. It is here that Jimmy meets Oryx in person for the first time. Oryx and Jimmy eventually develop a sexual relationship even though Oryx is also in a relationship with Crake. The arrangement is odd, but Crake does not seem to know about it.
Oryx's job is to both teach the Crakers about botany and market the BlyssPluss Pill. One day, a worldwide pandemic breaks out. Oryx realizes that it is emerging from every city that she had visited to market the pill. Jimmy locks himself into the Paradice compound with the Crakers. When Crake, who had been out at an unknown place returns, he is unable to get in. When Jimmy lets him in, Crake slits Oryx's throat in front of him. Jimmy then shoots Crake.
The world slowly fades as Jimmy hides out in the Paradice complex. He watches the television stations turn to static. Eventually he realizes that he has to leave the complex because the electricity will run out and he will be trapped inside of the electronically locked doors. He introduces himself to the Crakers as a messenger from Crake and a friend of Oryx. He exits the complex with the Crakers and relocates them to a beach side park.
Once there, he builds a small habitat for himself in a tree. It is here that he begins to deteriorate because he runs out of food and entertainment. He is alone among a group of strange creatures that know nothing of the world prior to the viral pandemic. He notes that the Crakers exhibit some of the qualities that Crake initially tried to edit out. It is during this time that Snowman, as he has identified himself to the Crakers, begins to narrate his story.
Snowman realizes that he will die if he does not find more sources of food. As such, he decides to return to the compound for supplies. On his way there, he runs into numerous obstacles and hurts his foot. He hides from a group of pigoons in a watchtower room. It is there that he hears voices over the radio and first learns that he is not alone. He arrives at the complex and raids it for whatever supplies and food he can carry. His foot becomes badly infected.
Upon his return to the Craker encampment by the beach, he is told that three other humans recently passed by. Snowman is disturbed by this knowledge because he knows that he has promised both Oryx and Crake to take care of the Crakers. On the other hand, he does not want to have to harm the humans. The book closes with Snowman's approach toward the three humans. What he ultimately decides, is not revealed to the reader.