A pseudo-autobiography of how the author imagines his future, Slapstick takes place in an apocalyptic future as Wilbur Daffodil-11 Swain, a former pediatrician and President of the United States, writes a memoir of his life at 100 years old. The story skips around to different periods but is generally told chronologically to explain his current existence in the Empire State Building on the solitary island of Manhattan.

Wilbur's childhood is unusual. Born in a set of physically deformed twins, he and his sister Eliza are assumed mentally retarded with short life expectations. Their very wealthy parents fix up an old mansion in Vermont and the locals and a family practitioner care for the children while the parents visit once a year and on birthdays. Wilbur and Eliza quickly educate themselves through the many books in the mansion. While Eliza never grasps reading and writing, she is a creative problem-solver, while Wilbur is very analytical and can read and write. When they are in close proximity to each other, their minds meld to create a 'genius' that becomes the author of several masterpieces of writing and invention. However, they become so consumed by the genius, that they often lose themselves in an incestuous orgy, grasping to get intellectually even closer to each other. When separate, they refer to themselves as Bobby and Betty Brown, boring and inconsequential sorts.

Wilbur and Eliza hide their intelligence, as it seems what is expected of them. However, on their fifteenth birthday they overhear their mother express her hatred for them. She thinks she could endure her role better if her children showed one glimmer of intelligence. Wilbur and Eliza expose the truth, which shocks the whole household. They are tested but after exhibiting one of their genius orgies, Wilbur is sent to a private school for mentally disturbed boys and Eliza is sent to an institution. Wilbur soon forgets his sister as he becomes accepted into medical school and leads a busy, affluent life. After their father dies, Eliza appears to claim her inheritance. She thrashes out in anger at Wilbur and their mother in the press. Eventually, she visits Wilbur and before long, their minds are reunited into the genius. This time, the orgy lasts five days and they both end up comatose. Realizing the danger of being together, Eliza moves to Machu Picchu and never physically sees Wilbur again.

Wilbur graduates from Harvard Medical School and becomes a pediatrician, using a book he and his sister wrote on parenting as a 'genius' as his main guide for patient care. At one point, he is visited by a miniature Chinese man who is interested in 'genius' writings that Eliza and Wilbur hid in the mansion. Wilbur agrees to show him the works and the Chinese man is particularly interested in their papers on gravity. Eliza gets a trip to Mars, which the Chinese have colonized, as a reward. Not long after, Wilbur receives a letter informing him about Eliza's death in an avalanche on Mars. At that moment, there is a massively oppressive gravity shift and the world is changed forever. Machinery becomes almost defunct as major cities fall to ruin. Machu Picchu falls into the ocean. That day, Wilbur takes a drug called tri-benzo-Deportamil and becomes addicted to it for almost thirty years.

Wilbur married and divorced as a doctor, unable to love his wife or son. He changes careers and runs political campaigns proclaiming he will end loneliness for all Americans. He wins the campaign for President and institutes his plan, which he and Eliza had conceived as children. Every person is assigned new middle names, and those that share a middle name are instantly related. Wilbur believes that large, extended families are the cure to loneliness. His plan indeed seems to have a good effect as crime drops and family clubs and newsletters pop up around the nation. Wilbur discovers the White House dishwasher is now his brother. Everything is going along grandly.

Wilbur marries and divorces again, but gravity shifts continue (though not to fatal degrees), and a plague strikes the nation. Most of the population is killed off. New York has its own version of the plague, known as the Green Death, and is hence nicknamed the Island of Death. All the White House staff either dies or disappears, except for Wilbur and the dishwasher. His presidency is forgotten. One day a pilot and frontiersman appear. The frontiersman has a letter inviting him to visit a widow in Indiana whose husband had discovered a way to communicate with the afterlife. The pilot agrees to take Wilbur and the Dishwasher to Indianapolis where the Daffodil family members primarily live. They are given a grand welcome and Wilbur feels good about the results of his extended family plan. The Dishwasher is left there with family while Wilbur visits the widow. Her husband had discovered he could communicate with the dead through a pipe-like device nicknamed the Hooligan. Wilbur is able to communicate to Eliza through it. She tells him that the afterlife is terribly dull and he must kill himself at once to help her figure out a way to make it better. Wilbur gives away his last remaining pills of tri-benzo-Deportamil and has sex with the widow during his arduous withdrawal period.

The pilot takes Wilbur to New York where Wilbur assumes he will die of the Green Death and join his sister. However, he is found by the Raspberry family who need a doctor and is given an antidote. He helps cure a Raspberry man of an illness and is given a candlestick as a present. After that, people always give him candlesticks. He amasses over 1000 and becomes known as the King of Candlesticks. However, there are no candles in New York. Over the years, Wilbur befriends a neighbor named Vera who has a farm with slaves and raises animals and produce. Eventually, a 12-year old girl named Melody shows up claiming to be his granddaughter. Her father was the son conceived by Wilbur and the widow many years before. She is pregnant from being raped but the child is stillborn. Melody finds a lover, Isadore, and he helps her build a pyramid over the baby in the streets of New York. She also becomes pregnant by him at the age of 16. Vera has a grand party for Wilbur's 100th birthday and he is given 1,000 candles made by the slaves. They light them all in the lobby of the Empire State Building and Wilbur feels as if he is a god in the galaxy. It is the last entry in his memoir as he dies soon after, presumably rejoining Eliza in the afterlife.