Seveneves is a speculative novel dramatizing humankind's effort to survive following the Moon's explosive fragmentation by some inexplicable agent. Astronomers estimate only two years remain before debris enters and burns away Earth's atmosphere, surface, oceans, and all life. The International Space Station, fitted with "arklets," populated with 1,500 people and the Human Genetic Archive, is the foundation around which the Cloud Ark will be constructed. The brain-trust is tasked by leaders to engineer a self-sustaining environment capable of maneuvering away from larger fragments, and withstanding 5,000 years in near-earth orbit until the planet is stable enough to be terraformed into supporting life. The project is designed also to engage those left behind, and prevent worldwide chaos.

In present-day Utah, an amateur astronomer notices a dusty blur near the Moon's equator, and is thrilled to blog about it on his phone. Before he can thumb the first key the Moon no longer exists. He and millions of others throughout the Americas witness the same chilling sight: a greater-than-moon-sized cloud which, after the dust settles, turns red. After that, 7 tumbling boulders still bound by gravity remain. World leaders in science, defense, and politics are mystified, referring to the causal Agent. No one knows, and the conspiracy-minded suspect extraterrestrial forces are responsible, but are not taken seriously. Scientists are confident the Agent will be identified.

In northern Alaska, miner Rufus MacQuarie sees the cataclysm from high atop the Brooks Range, and consults an app that displays current positions of both natural and man-made celestial objects. Checking for the International Space Station, he lashes to his knee a self-designed telegraph key and taps a message—LOOK AT THE MOON—to his daughter, Dinah, a roboticist on the ISS (known as "Izzy" to occupants). Dinah does this and, along with the rest of humanity, knows the universe is forever changed. Later (A+0.0.4: zero years, zero days, and four hours after the event) at a meeting in the ISS between Commander Ivy Xiao, Dinah, and the ten other crew members, German astronomer Konrad Barth theorizes that a Primordial Singularity, or small black hole, hit the moon like a bullet through an apple.

Dubois "Doob" Jerome Xavier Harris, Ph.D. observes the moon's destruction during a fund-raiser at Caltech Athenaeum. His role as TV's Dr. Harris—popularizer of science—asserts itself, and he soon is besieged with requests to "explain" why scientists missed the approaching "meteorite." His phrase "breakup of the moon" (not explosion) becomes popular on Twitter—hashtag #BUM. The largest moon fragments are named the Seven Sisters. Harris himself benignly names them Potato Head, Mr. Spinny, Acorn, Peach Pit, Scoop, Big Boy, and Kidney Bean. Scientists speculate these tremendous remnants will repeatedly collide and produce an infinite number of smaller material destined to enter Earth's atmosphere in approximately two years. They name the debris cloud "white sky," precursor to the unimaginable apocalypse of "hard rain" when the mass becomes super-heated bolides (bright fireballs) smashing into the planet and causing the oceans to boil away. In one week various star parties are given, during which the public and school buses full of children visit parks and make a game out of identifying by shape and name the Seven Sisters. An optimistic theory circulates, claiming the moon's gravity will gradually draw together all the fragments, but vivid meteor showers seem to contradict this notion. At a Caltech campus party, Dr. Harris meets elementary school teacher Amelia Hinojosa, and they fall in love.

Dr. Harris meets with U.S. president Julia Bliss Flaherty, and tells her it's crucial to stop asking what happened, and start talking about what's going to happen. It is decided that the only places anyone might survive are in space, or deep underground. An ad hoc committee of spacefaring nations establishes a project of immense scale: the International Space Station will serve as the hub around which will be constructed a Cloud Ark consisting of hundreds of "arklets," prefabricated "cans" rotating in pairs for artificial gravity. These will support the last people to escape Old Earth, as well as the vital Human Genetic Archive. The ISS is attached to a captured Arjuna (near-Earth) asteroid, Almathea, which is being mined for nickel and iron by Dinah MacQuarie's robots. It is decided these metals can be smelted and used to produce building materials. The President's Science Adviser, Dr. Pete Starling, is as devastated as everyone else when informed that the Cloud Ark must be self-sustaining for 5,000 to 10,000 years. Entrepreneur Sean Probst, Dinah's boss, founder and chairman of Arjuna Expeditions, plans to head an operation to capture and bring back to ISS a comet—Grigg-Skjellerup ("Greg's Skeleton")—formed of ice, which will provide drinking water and can be used as a propellant for "Izzy's" thrusters. The mission will require a small nuclear reactor. Latent radioactivity in the spacecraft's fuel rods will convert comet ice into steam.

Authorities on Earth, including NASA, paint the moon's destruction with false sentiment and "cute" terms. The public is urged to assist the Cloud Ark project, but are not aware that only 1,500 people ultimately will be selected by a supposed Casting of Lots; the mass activity is designed to assuage despair and lessen chances of rioting and other violence. The predicted "hard rain" starts 701 days after the moon's shattering, and Earth's surface is annihilated. Dinah's father, Rufus MacQuarie, and some others have made one of his company's Alaska mines into a well-equipped fortress. Ivy Xiao's fiancé, Navy submarine commander Cal Blankenship, has headed with his crew for a deep-sea trench. None—including government/military leaders in vast subterranean holdouts—are expected to survive.

The greatly enhanced ISS crew, most of whom occupy arklets, have little time to carry out final communications with loved ones and must maneuver the Cloud Ark away from debris as well as deal with last-minute "stragglers" (the U.S. president, Julia Bliss Flaherty, among them) who managed to launch into space during the brief "white sky" period. On the ground, doomed people gather in places of worship and elsewhere, while choirs and orchestras are broadcast over the sizzling airwaves until silenced by the deadly bolides.

Not long after, Swiss astronaut Markus Leuker replaces Ivy as commander of the Ark, and announces that all political/national allegiances no longer hold, and declares what amounts to martial law pursuant to the Crater Lake Accord—a sort of new Constitution prepared on Earth during the massive production of materials in Seattle. As a contingency/safety measure, the Ark as yet has no command center. Any tablet (accessed with the correct password) can be used to control the station's thrusters, and network specialists design social media platforms: Scape, for video-conferencing; Spacebook for more recreational matters; and a cell-phone system. Political concerns manifest as they did in earthbound times, and three factions emerge. Swarmamentalists, who want "pure swarm," i.e., the genetics lab and materials distributed among the arklets, which would then collectively move to a higher orbit relatively safe from lunar debris. A second group holds a "Dump and Run" perspective—jettison most of the attached asteroid (Amalthea), and robotically hollow out the remainder into a protective human nest. The third faction—the Big Ride—is most ambitious: boost the station and Amalthea to a much higher orbit, and feed off the icy comet Sean Probst's mission promises to deliver. The ultimate, permanent, destination is a massive iron moon remnant scored with a Grand Canyon-sized zone named Cleft. There, no latent debris or ubiquitous micrometeoroids can penetrate, and humankind can start over.

When former U.S. President Julia Flaherty recovers from a harrowing (and illegal) docking with the Ark, her assertive temperament and ideas attract followers, and yet another group is formed: those who have hoarded supplies into a handful of arklets and plan to colonize Mars. Sean Probst's Ymir spacecraft completes a half-year journey to capture the "Greg's Skeleton" comet. He manages to head the operation toward the Ark, and he and his six-person crew perish from radiation poisoning. In a Modular Improvised Vehicle (MIV) christened New Caird, Markus, Dinah, nuclear engineer Jiro Suzuki, and Vyacheslav Dubsky are able to dock with the ghost ship Ymir and ascertain it is on course to orbit with the Cloud Ark. Dinah is the sole survivor of this mission, but now the Ark is assured of water for propellant and drinking. Julia Flaherty and most of the station's occupants abandon the vessel, head off in arklets to a safer orbit, and start the long journey toward Mars. After so much death, division, and brutal hardship, those remaining on the Ark rechristen it as Endurance.

After Endurance (formerly the ISS) is fitted with the immense ice "splinter" captured by tragically heroic Sean Probst and his crew, the new mass burdens the projected one-year, 300,000-mile journey to Cleft into three years. Only nine people survive, and Dr. "Doob" Harris dies after a final "moon-walk." The surviving eight are all women, and hold a meeting—the Council of the Seven Eves—to decide whether to continue existing. They are called the Seven due to Luisa's having passed menopause. With the Human Genetic Archive gone, Moira explains that, using automictic parthenogenesis, uniparental embryos can be created out of normal eggs. Thus—barring further catastrophe—the human race will be reborn.

After 5,000 years, several billion people (descended from the Seven Eves: Dinah, Ivy, Moira, Camila, Julia, Tekla, Aïda) live in the Great Chain, a ring of orbiting habitats. Members of Survey and Snake Eaters are tasked with monitoring and reporting on the growth of New Earth's ecosystem which, after millennia of seeding using manipulated DNA preserved from Old Earth and oceans replaced with melted comet ice, is nearly ready for human reoccupation. Some, whose DNA was repurposed long ago by Eve Moira, are capable of epigenetic adaptation. More conservative inhabitants, Amistics, are ambivalent about constantly evolving technology. Primarily, humankind is divided into two factions: Blue, aligned with the traditions of Endurance, and Red, following Swarm beliefs and philosophies. In spite of treaties, a group labeled as Sooners take it upon themselves to relocate to Earth. Further problems arise when reports of anomalous people on Earth spark the creation of Seven, an investigatory group comprised of one member from each of the new human races. It is discovered that some people, well-prepared in the two years following the moon's disintegration, survived. Diggers (descended from Eve Dinah's father), who built underground holdouts; and Pingers (descended from Eve Ivy's fiancé), who guided submarines into the deepest undersea canyons. These survivors evolved into two races, the Pingers capable of underwater exploration, where the ejecta of "Spacers" are discovered.

The orbiting human races fight over exclusivity of contact with the survivors, and discover means of communication with them. Once established, more conflict manifests from the Diggers. At length, it is understood that yet further disagreements and even violence will forever mark the races of humankind, wherever they may travel.