The narrator of Cat's Cradle, John, once set out to write a book, titled The Day the World Ended, about the day the atomic bomb was dropped on Hiroshima. For purposes of research, he wrote to Newt Hoenikker, the midget son of Felix Hoenikker, the Nobel prize-winning physicist and one of the fathers of the atomic bomb. He asked Newt to describe what he remembered from the day the bomb devastated Hiroshima. Newt replied to say that he was only six years old when the bomb was dropped. He remembers playing with his toy trucks while his father played cat's cradle with a piece of string.

Newt explained that Felix never showed any interest in people, so when Felix sat down to play with him that day, it was highly unusual. Felix looked so huge, ugly, and frightening when he tried to show Newt the cat's cradle that Newt fled the house in tears to sit with his brother, Frank, who was making various bugs war against one another in Mason jars. Angela, Newt's six-feet-tall sister, scolded Newt for hurting Felix's feelings, but Newt continued to complain that Felix was ugly and scary. When she slapped Newt, Frank punched her in the stomach. Shortly after Newt replied to John's letter, the newspapers reported Newt's engagement to Zinka, a Russian midget dancer and rumored Soviet spy.

John traveled to Ilium, the town where the Hoenikkers lived during World War II, to continue researching his book. Some high school classmates of Frank Hoenikker told John that Frank was a strange, reclusive, secretive youth. Frank's main interests included building models and working at Jack's Hobby Shop in town. His peers called him "Secret Agent X-9." In Ilium, John met Asa Breed, Felix's former supervisor at the Research Laboratory. Asa informed him that Emily Hoenikker, Felix's wife, suffered an injury to her pelvis during an automobile accident. He attributed her death in childbirth to this injury.

Asa gave John a tour of the Research Laboratory while John interviewed him. Asa praised Felix's ability to put his analytical, scientific mind to any task. Once, a general asked Felix to produce a solution to mud, a constant problem for troops on the move. Felix theorized the existence of an isotope of water, which he named ice-nine, that was solid at room temperature. Even the smallest seed of ice-nine dropped into a quagmire would solidify the mud and solve the problem. John, realizing that such an action could easily lead to the freezing of all water on earth, nervously asked if Felix had actually succeeded in creating ice-nine, a deadlier threat to life on earth than the atom bomb. Asa denied it, but he angrily ended the interview because he sensed that John thought scientists were cold-hearted and dangerous.

After his ill-fated interview with Asa, John visited the local cemetery to take a photograph of Felix's grave. He found that Emily Hoenikker's tombstone was a 20-foot high monument while Felix's tombstone was a small, modest square marker. He learned from Martin Breed, proprietor of the local tombstone store and brother of Asa Breed, that Angela and Frank came to his store and bought Emily's tombstone a year after her death because Felix hadn't bothered to buy one for her. Martin hated Felix, despite the prevailing notion that Felix was harmless and innocent. He did not believe any man who had a hand in creating the atom bomb could be innocent; Martin had also been in love with Emily, his high school classmate. He implied that Emily was miserable in her marriage to Felix, owing to Felix's lack of concern for other people and their feelings.

Unbeknownst to John, Felix had indeed created ice-nine, without keeping records of his discovery. Shortly before he died, on Christmas Eve at Cape Cod, he showed the isotope to his children. The Hoenikker siblings divided the ice-nine among themselves. Frank used it to buy himself a comfortable job as Major General on the island republic of San Lorenzo. Angela traded hers in exchange for marriage to the handsome Harrison Conners, a scientist employed in top-secret weapons research for the United States. Zinka stole Newt's share of ice-nine for the Soviet government.

Meanwhile, John was hired to write an article about Julian Castle, a multi- millionaire philanthropist living on San Lorenzo. On the plane to the island, John met Lowe and Hazel Crosby and Horlick and Claire Minton. Lowe and Hazel were traveling to San Lorenzo to open a bicycle factory because the island legislated no labor restrictions. Horlick was the new American ambassador to San Lorenzo. Angela and Newt also occupied the plane; they were en route to a celebration of Frank's engagement to Mona, the beautiful adopted daughter of "Papa" Monzano, the island's dictator.

All of San Lorenzo's residents were practitioners of Bokononism, a religion created by Bokonon. When Bokonon and his friend McCabe first arrived on San Lorenzo, they wanted to make the island into a utopia. San Lorenzo had a tumultuous history, conquered and claimed by various nations at various times. The island was completely worthless. When McCabe and Bokonon asserted their authority, no one intervened. McCabe and Bokonon quickly realized that no amount of legal and economic reform would provide the island's residents with a good standard of living. Instead, Bokonon offered the inhabitants of the island comfort through the creation of an eponymous religion based on happy lies. At Bokonon's request, McCabe outlawed Bokononism and made its practice punishable by death. Thus, outlawed, the religion gave excitement and a comprehensible meaning to the lives of the island's impoverished masses. Every ruler since then, including, Papa Monzano, participated in the charade.

On the island, Monzano, stricken with terminal cancer, named Frank his successor. Uninterested in the responsibilities of the job, Frank asked John to take his place as San Lorenzo's next President. John refused the position until Frank told him that he would get to marry Mona as part of the bargain. Monzano gave his blessing to the plan and wished them luck before taking the Bokononist last rites. John briefly considered lifting the ban on Bokononism, but he realized that he did not have the ability to offer adequate food, housing, and social services to the populace. Therefore, he decided to continue the charade of his predecessors.

During the ceremony in honor of San Lorenzo's Hundred Martyrs to Democracy, John planned to announce his assumption of the Presidency. During the ceremony, Monzano's attending physician, Dr. von Koenigswald informed him that Monzano had committed suicide. Upon looking at the body, John realized that Monzano's condition could only have been caused by swallowing ice-nine and that, by extension, Felix's experiments to create the isotope had been successful. When John demanded that Frank, Newt, and Angela come to Monzano's bedroom, they confessed that they had divided Felix's awful creation among themselves after he died, though they couldn't explain why. They set about cleaning the room by melting the fragments of ice-nine. They decided to take a break before burning the bodies to go watch the ceremony for the Hundred Martyrs. During the ceremony, a plane crashed into the cliffs above Monzano's castle. A landslide ensued, taking half the castle along with Monzano's body into the sea. All the water of the world became ice-nine within seconds.

Shortly after the disaster, most of the island's survivors, including Mona, committed suicide. John, Frank, Newt, and the Crosbys survived for six months. John wrote this narrative, Cat's Cradle, as a record of what had occurred, while Newt painted, Hazel sewed, Lowe cooked, and Frank studied ants. Bokonon finished writing the Books of Bokonon, all the while commenting on human stupidity.