The story is written in first-person perspective by the geologist William Dyer, a professor at Miskatonic University. He writes to disclose hitherto unknown and closely kept secrets in the hope that he can deter a planned and much publicized scientific expedition to Antarctica. On a previous expedition there, a party of scholars from Miskatonic University, led by Dyer, discovered fantastic and horrific ruins and a dangerous secret beyond a range of mountains higher than the Himalayas. The group that discovered and crossed the mountains found the remains of 14 ancient life forms; completely unknown to science and unidentifiable as either plants or animals. Six of the specimens are badly damaged and the others uncannily pristine. Their highly-evolved features are problematic: their stratum location puts them at a point on the geologic time scale much too early for such features to have naturally evolved yet.
When the main expedition loses contact with this party, Dyer and the rest of his colleagues travel to their camp to investigate. The camp is devastated and both the men and the dogs slaughtered, while Gedney (another member of the sub-expedition) and a dog are missing. Near the camp they find six star-shaped snow mounds, and one specimen buried under each. They discover that the better preserved life forms have vanished, and that some form of dissection experiment has been done on a deliberately unnamed man and a dog. Dyer elects to close off the area from which they took their samples.
Dyer and a graduate student named Danforth fly an airplane over the mountains, which they soon realize are the outer wall of a huge, abandoned stone city of cubes and cones, utterly alien compared with any human architecture. Because of their resemblance to creatures of myth mentioned in the Necronomicon, the builders of this lost civilization are dubbed the "Elder Things". By exploring these fantastic structures, the men are able to learn the history of the Elder Things by interpreting their magnificent hieroglyphic murals: The Elder Things first came to Earth shortly after the Moon was pulled loose from the planet and were the creators of life. They built their cities with the help of "Shoggoths", biological entities created to perform any task, assume any form, and reflect any thought. As more buildings are explored, a fantastic vista opens of the history of races beyond the scope of man's understanding, including the Elder Things' conflicts with the Star-spawn of Cthulhu and the Mi-go who arrived on Earth some time after the Elder Things themselves. The images also reflect a degradation in the order of this civilization, as the Shoggoths gain independence. As more resources are applied to maintaining order, the etchings become haphazard and primitive. The murals also allude to some unnamed evil in an even larger mountain range just past their city which even they fear greatly. Eventually, as Antarctica became uninhabitable even for the Elder Things, they migrated into a large, subterranean ocean.
The two eventually realize they are not alone in the city. The Elder Things missing from Lake's camp had somehow returned to life and, after slaughtering the explorers, returned to the city of their origin. Dyer and Danforth discover traces of the Elder Things' earlier exploration, as well as sledges containing the corpses of Gedney and the dog missing from the camp.
As the two progress further into the city, they are ultimately drawn to a massive, ominous entrance which is the opening of a tunnel which they believe leads into the subterranean region described in the murals. Compulsively they are drawn in, finding further horrors: evidence of dead Elder Things caught in a brutal struggle and blind six-foot-tall penguins wandering around placidly, apparently as livestock for the unknown forms of life which lurked inside the subterranean abyss. They are then confronted with an immense, ululating horror in the form of a black, bubbling mass, which after a brief glimpse they identify as a Shoggoth. Danforth and Dyer escape with their lives using luck and diversion. On the plane high above the plateau, Danforth looks back and sees something that causes him to lose his sanity. He refuses to tell anyone (even Dyer) what he saw, though it is implied that it has something to do with what lies beyond the larger mountain range that even the Elder Things feared.
Professor Dyer concludes that the Elder Things and their civilization were eventually destroyed by the Shoggoths they created and that this entity has sustained itself on the enormous penguins since eons past. He begs the planners of the next proposed Antarctic expedition to stay away from things that should not be loosed on this Earth.
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