The story starts after the end of the world. Jimmy—who calls himself Snowman now—is the last normal human left on Earth, as far as he knows. The other inhabitants are the Crakers. The Crakers are genetically modified humans who were created to be peaceful, to live in harmony, and to die at the age of thirty before experiencing old age. Jimmy guides and teaches them while slowly going insane himself.

Jimmy reflects on his past. He grew up in a walled-off compound owned by a biotech company. His best friend was a boy named Crake. Neither of them had involved parents. Crake’s father died, and Jimmy’s mother left the family before being executed. Jimmy and Crake grew up together until they separated for college. Crake studied hard and took things seriously; Jimmy enjoyed the company of women, alcohol, and cigarettes. He had a number of affairs that left him feeling cold and empty.

Eventually, Crake hired Jimmy to work on the Paradice Project ad campaign. He said its focus was on immortality. One thing they worked on is the BlyssPluss Pill, designed to protect against STDs, extend youth, and make the person more sexually excited. It would also make many people sterile. When Crake took Jimmyto Paradice, it was the first time he saw the Crakers.

Oryx was the teacher of the Crakers. She was also in a relationship with Crake. She had been sexually abused in the past and was old as a slave. However, she was cheerful and wanted everyone to get along. At one point, she had an affair with Jimmy, because he was in love with her and she didn't want him to be unhappy about her.

One day, Jimmy saw the news of outbreaks of a hemorrhagic agent around the world. People were dying. Oryx called him crying and saying that she didn’t know. The BlyssPluss pills were actually a way to spread the disease. People all over the world were dying. Crake returned to the compound and slit Oryx’s throat, coaxing Jimmy to shoot him. This is how Jimmy ended up as the last person on Earth.

Jimmy watched society fall apart from Paradice. He waited to release the Crakers until all the humans were dead so they wouldn’t be exposed to the trauma of their deaths. Now that they are free, Jimmy spends his days caring for the Crakers and trying to teach them. He tells them stories with Oryx and Crake as their gods. He has an injured foot that isn’t healing properly.

Eventually, he finds out that some humans survived—at least three—and that they stopped to speak to the Crakers. Jimmy sets off to find (and possibly kill) the people. He isn’t sure what he's going to do when he sees them. The novel ends with the reader not knowing what he chooses.