Galápagos is the story of a small band of mismatched humans who are shipwrecked on the fictional island of Santa Rosalia in the Galápagos Islands after a global financial crisis cripples the world's economy. Shortly thereafter, a disease renders all humans on Earth infertile, with the exception of the people on Santa Rosalia, making them the last specimens of humankind. Over the next million years, their descendants, the only fertile humans left on the planet, eventually evolve into a furry species resembling seals: though possibly still able to walk upright (it is not explicitly mentioned, but it is stated that they occasionally catch land animals), they have a snout with teeth adapted for catching fish, a streamlined skull and flipper-like hands with rudimentary fingers (described as "nubbins").
The story's narrator is a spirit who has been watching over humans for the last million years. This particular ghost is the immortal spirit of Leon Trotsky Trout, son of Vonnegut's recurring character Kilgore Trout. Leon is a Vietnam War veteran who is affected by the massacres in Vietnam. He goes AWOL and settles in Sweden, where he works as a shipbuilder and dies during the construction of the ship, the Bahía de Darwin. This ship is used for the "Nature Cruise of the Century". Planned as a celebrity cruise, it was in limbo due to the economic downturn, and due to a chain of unconnected events the ship ended up in allowing humans to reach and survive in the Galápagos.
Kilgore Trout—deceased—makes four appearances in the novel, urging his son to enter the "blue tunnel" that leads to the afterlife. When Leon refuses for the fourth time, Kilgore pledges that he, and the blue tunnel, will not return for one million years, which leaves Leon to observe the slow process of evolution that transforms the humans into aquatic mammals. The process begins when a Japanese woman on the island, the granddaughter of a Hiroshima survivor, gives birth to a fur-covered daughter.
Trout maintains that all the sorrows of humankind were caused by "the only true villain in my story: the oversized human brain". Fortunately, natural selection eliminates this problem, since the humans best fitted to Santa Rosalia were those who could swim best, which required a streamlined head, which in turn required a smaller brain.