In "At the Mountains of Madness," the geologist William Dyer recounts his experiences leading a group of scholars from Miskatonic University on an expedition to Antarctica. The purpose of his narration is to warn against a future scientific expedition to the region. Dyer reveals that during their previous expedition, his team stumbled upon ancient ruins and a shocking secret hidden beyond the towering mountains.

A team led by Professor Lake makes a significant discovery. They uncover the remains of fourteen unknown life-forms, which cannot be classified as either plants or animals. Six of the specimens are damaged, but the other eight are perfectly preserved. The age of these fossils places them much earlier in the geologic time scale than expected, suggesting that the features of these specimens could not have evolved naturally. Furthermore, some of the Cambrian age fossils show signs of tool usage for carving specimens for food.

When the main expedition loses contact with Lake's party, Dyer and his graduate student, Danforth, decide to investigate. What they find is a scene of devastation at Lake's camp, with the majority of men and dogs brutally slaughtered. One man named Gedney and a dog are missing. Nearby, they discover star-shaped snow mounds, each containing a specimen. The well-preserved life-forms have disappeared, and there are signs of dissection experiments performed on a man and a dog. Gedney is suspected of going insane and committing these gruesome acts.

Flying over the mountains, Dyer and Danforth come across an ancient stone city that appears alien to human architecture. These structures are reminiscent of creatures of myth mentioned in the forbidden book, the Necronomicon, and they are referred to as the "Elder Things." As they explore the city, they find hieroglyphic murals that reveal the Elder Things arrived on Earth long ago, soon after the formation of the Moon. These beings built their cities with the help of "shoggoths," versatile entities capable of performing any task and assuming any form. It is suggested that all life on Earth evolved from cellular material left behind by the creation of these shoggoths.

Continuing their exploration, Dyer and Danforth learn about the Elder Things' conflicts with other alien races such as the Star-spawn of Cthulhu and the Mi-Go. The murals also depict a degradation of the Elder Things' civilization as the shoggoths gain independence. They uncover hints of an unnamed evil residing in a vast mountain range beyond the city, which the Elder Things avoided exploring. Eventually, when their own civilization faced destruction in an uninhabitable Antarctica, the Elder Things migrated to a large subterranean ocean.

Dyer and Danforth make a shocking discovery when they realize that the missing Elder Things from Lake's party have come back to life and returned to their city. Traces of their earlier exploration are found, along with Gedney's and his dog's corpses. Venturing deeper into tunnels depicted in the murals, they stumble upon evidence of a violent struggle and encounter shoggoths. They narrowly escape the clutches of a black, bubbling mass, believed to be a shoggoth, and flee using their plane. As they ascend, Danforth witnesses something that drives him to insanity, possibly the unnamed evil itself.

Dyer concludes that the Elder Things, survivors from a distant era, only attacked Lake's group out of self-defense or scientific curiosity. They were ultimately destroyed by the shoggoths, which now prey on the massive penguins inhabiting the region. Dyer strongly advises against any future expeditions to the site, warning of the danger they may encounter.