Four nameless women cross the border into Area X, which has been contained for thirty years by the mysterious Southern Reach agency. The story of what happens next is recorded by the biologist in her field journal. She and her companions—an anthropologist, a surveyor, and a psychologist—are all part of the twelfth expedition into Area X. The biologist joins the expedition in part because of her husband's participation in the eleventh expedition. After being missing for a year, he returned to their home one night with little recollection of the trip or of how he had suddenly found himself back across the border. The same strange fugue is repeated by the other seven members of his expedition. The biologist's husband died six months after his return from the same inoperable cancer suffered by the other members of his expedition.
Team Twelve's first night at base camp is uneventful, except for the discovery of a spiral staircase that goes into the ground, which the biologist refers to as a tower. They discover cursive lettering on the interior walls of the tower composed of living fruiting bodies. The writing seems biblical, like something out of Revelations. The biologist accidentally inhales a burst spore from the plants while taking a closer look, but withholds the incident from the rest of the team. Back at base camp, she learns that the team members have all been programmed with certain triggers by the psychologist, who is the pre-chosen group leader. One of these phrases is "consolidation of authority" and when she says this the team immediately falls into a trance-like sleep, but the triggers do not work on the biologist and she suspects that the spores she inhaled might have made her immune to the effects of hypnosis.
The morning after discovering the tower, the biologist sees that the anthropologist has gone missing. The psychologist tells her and the surveyor that the anthropologist was unable to withstand the rigors of the trip and has already gone back across the border. The remaining explorers go back to the spiral staircase where the psychologist stands watch while the other two descend. They find the anthropologist dead at the bottom and assume that she was killed after meeting the writer of the phrases on the side of the staircase. The biologist begins to refer to the writer in her field log as "The Crawler." While still in the depths of the tower, the biologist tells the surveyor her theory about the psychologist. She believes the psychologist coerced the anthropologist to approach the unidentified organism, thus leading her to slaughter. The surveyor doesn't believe the biologist at first, and cautiously maintains faith in the psychologist as the leader of their expedition. When they ascend to the top of the tower the psychologist is nowhere to be seen. They search for her, but after failing to find her they decide to return to base camp, where they discover the psychologist has taken half the supplies and most of the firearms. As the biologist goes to sleep she sees a light emanating from the lighthouse.
In the morning the biologist prepares to set out to find the lighthouse on her own. The surveyor will stay behind, wishing that they would simply hike back to the border and await extraction. She begrudgingly promises to wait a day for the biologist to return, after which she will be free to hike back to the base alone. When the biologist arrives at the lighthouse, it turns out to be a treasure trove of information. She finds a midden (dumpsite) filled to the brim with journals written by members of previous expeditions—far more than they had been told about. She even finds her husband's field journal. The psychologist is also at the lighthouse, injured, and seems scared of the biologist. She keeps screaming "Annihilation!" as the biologist approaches, which the biologist later finds out is a trigger word that is intended to induce suicidal feelings in the biologist. It doesn't work, and the psychologist tells her that she was injured as a result of jumping off the top of the lighthouse running away from something; she doesn't know what it was. She tells the biologist that the border is expanding northwards and she begins to see a yellow light glowing around the biologist.
Every night, the biologist has heard an animal moaning outside of base camp; on the way back from the lighthouse she finally has an encounter with it, and after narrowly escaping, she runs into the surveyor who is shooting at her. She fires back, and manages to kill the surveyor, although she is injured herself. She takes the time to go over everything she has found on the way back from the lighthouse and also starts to read her husband's journal. His team consisted of eight members, and their approach was somewhat different from that of her team. Although they had found the staircase, they hadn't explored it, choosing instead to concentrate their efforts on the lighthouse. After finding a mass of journals, they split up. Two explored the staircase, four the lighthouse, and her husband went on further to the land past the lighthouse. Area X seemed to stretch out into infinity, so they returned to the staircase but were unable to find the other two men. They then saw doubles of the entire team, including themselves, entering the tunnel. This convinced them to abandon the mission and go home, but they split up first. The biologist's husband found a boat and tried to cross back along the shoreline.
The biologist decides to search for the Crawler in the tunnel. She finds it, but it nearly kills her. She continues on but when she turns around she sees the face of the former lighthouse keeper looking back at her. She decides that she will not return home. Instead, she will follow the path her husband laid out in his journal, hoping if not to find him, at least to see what he saw.
