The narrator, Jonah, plans to write a book, The Day the World Ended, describing what important people were doing the day the atomic bomb was dropped on Hiroshima. His research prompts him to contact Newton Hoenikker, the youngest child of Felix Hoenikker, a fictional Nobel laureate physicist who helped develop the weapon. Newt, though only a child on the day the atom bomb was dropped, remembers his father as a brilliant and distant man. Newt also mentions that his brother Frank has been missing for many years, but he provides Jonah with his sister Angela's contact information so that she can share her memories of the day in question. Jonah's attempts to contact Angela go unanswered, but eventually he gets a freelance writing job in Ilium, N.Y., where Felix worked and lived for most of his life.
While in Ilium, Jonah speaks with many of the city's individuals about the infamous Hoenikker family. The children's old colleagues remember them as outcasts and their father as an absent-minded weirdo. Dr. Asa Breed, Felix's former supervisor, and Felix's other colleagues seem to appreciate Felix's contributions to science, but they all tell stories of the ways in which he seemed incomplete or inhuman. He is characterized by his lack of interest in his children and wife, Emily Hoenikker, and many townspeople express dismay at his seeming lack of understanding of basic human emotions and feelings, especially love.
While in Ilium, Dr. Breed tells Jonah about a substance called ice-nine. The substance was a brainchild of Felix Hoenikker, but to Dr. Breed's knowledge he never actually created it. Dr. Breed explains that if a crystal of ice-nine were brought into contact with liquid water, it would change the liquid into a solid form of ice with a very high melting point. Although Jonah does not know it yet, the substance was actually created by Felix Hoenikker and inherited by the Hoenikker children after their father's death.
Shortly after Jonah's visit to Ilium, he receives a writing assignment on the island of San Lorenzo, one of the world's poorest countries. Before he leaves, Jonah learns from a magazine that Frank Hoenikker is also on the island of San Lorenzo working as a member of their government and is expected to be the successor to the island's ailing dictator. It is also through that magazine that Jonah first sees and falls in love with Mona Monzano, the adopted daughter of the island's ruler, "Papa" Monzano. Jonah believes she is the most beautiful woman on earth. On a plane to the island, Jonah finally meets Newton and Angela Hoenikker in person--they are also traveling to the island to celebrate their brother's engagement. Jonah is heartbroken to learn that Frank's engagement is to Mona Monzano. Jonah also begins to learn about Bokononism, a religion that was started by a man named Bokonon to give the people of San Lorenzo hope, despite their pitiful existence.
After a brief and spiritless celebration to commemorate the travelers' arrival, Jonah journeys to his hotel. He is surprised to find he is the first and only guest there (a few of his traveling companions decide to stay at the U.S. Embassy in response to a negative conversation with the hotel's owner). The hotel's owner, Philip Castle, grew up with Mona Monzano and was tutored by Bokonon in his childhood, and he introduces Jonah to some of the basic tenets of Bokononism. Later, Jonah travels to Frank Hoenikker's house, where he speaks with Newton about Dr. Hoenikker and learns that Angela is frustrated by the lack of recognition she believes her father got for his work. She views her father as a saint, and she seems unconcerned with the personal deficiencies that others have described about him.
When Frank arrives home, he convinces Jonah that he would be a better President than Frank, and Frank instructs Jonah that if he became President he would get to marry Mona. After a long discussion, Jonah agrees to become the new President of San Lorenzo. Jonah and Frank decide to announce his succession the next day at the memorial service for the Hundred Martyrs to Democracy.
During the celebration the next day, Papa is very close to death, so Frank and Jonah meet with him. When Papa learns that Jonah will be succeeding him, he makes Jonah promise that he will catch Bokonon. To Papa, science is the only real truth, and the people of the island should only learn scientific truths. Papa calls for his last rites, but when the Catholic priest arrives, Papa turns him away and asks for a Bokononist priest. Jonah leaves to attend the ceremony but is soon called back to Papa's bedside. When he returns, he finds Papa completely frozen with his fingers to his mouth, still poised from swallowing the piece of ice-nine that Frank had given him. Realizing that ice-nine both exists and was used by Frank to obtain power in San Lorenzo, Jonah calls the Hoenikker children to Papa's room. It is revealed that they all have used ice-nine in attempts to find happiness. Moreover, though it was supposed to be a secret, both the U.S. and Russian governments learned of the invention. Angela's husband, a government worker, had married her for possession of ice-nine, and Newt's ex-fiance was actually a Soviet spy who stole part of his piece.
Jonah and the children attempt to clean up Papa's corpse, but there is a disaster at the Hundred Martyrs to Democracy ceremony that causes a plane to crash into Papa's castle, damaging it enough to send his body flying into the ocean. When his body touches the water it instantly turns to ice-nine, causing a chain of ecological disasters. Jonah and Mona escape to a shelter in the remnants of the castle, where they stay for a few days. When they leave the shelter, they discover that the entire ecosystem has been destroyed and tornadoes fill the sky. They search for survivors and discover that almost all of the island's inhabitants traveled to a volcano on the island and committed suicide by swallowing ice-nine. At this sight, Mona laughs and decides to join her people by committing suicide as well.
Newt and a couple of other travelers find Jonah crying beside Mona's corpse a little while later, and they take him back to Frank's house. They have set up a refuge there, where they are able to live as if life as they knew it had not ended. They live there for months, until one day Jonah encounters Bokonon on another part of the island. He is surprised to see the prophet, who informs Jonah that he has written his last addition to the Books of Bokonon. As he reads his final entry aloud, Bokonon closes the novel with a reinforcement of his lack of reverence for life.