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The Horned Serpent appears in the mythologies of many Native Americans. Details vary among tribes, with many of the stories associating the mystical figure with water, rain, lightning and thunder. Horned Serpents were major components of the Southeastern Ceremonial Complex of North American prehistory.

Horned serpents also appear in European and Near Eastern mythology.

Horned serpents appear in the oral history of numerous Native American cultures, especially in the Southeastern Woodlands and Great Lakes.

Muscogee Creek traditions include a Horned Serpent and a Tie-Snake, estakwvnayv in the Muscogee Creek language. These are sometimes interpreted as being the same creature and sometimes different — similar, but the Horned Serpent is larger than the Tie-Snake. To the Muscogee people, the Horned Serpent is a type of underwater serpent covered with iridescent, crystalline scales and a single, large crystal in its forehead. Both the scales and crystals are prized for their powers of divination. The horns, called chitto gab-by, were used in medicine. Jackson Lewis, a Muscogee Creek informant to John R. Swanton, said, "This snake lives in the water has horns like the stag. It is not a bad snake. ... It does not harm human beings but seems to have a magnetic power over game." In stories, the Horned Serpent enjoyed eating sumac, Rhus glabra.

Alabama people call the Horned Serpent, tcinto såktco or "crawfish snake," which they divide into four classifications based on its horns' colors, which can be blue, red, white, or yellow.

Yuchi people made effigies of the Horned Serpent as recently as 1905. An effigy was fashioned from stuffed deerhide, painted blue, with the antlers painted yellow. The Yuchi Big Turtle Dance honors the Horned Serpent's spirit, which was related to storms, thunder, lightning, disease, and rainbows.

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