Plains Indians or Indigenous peoples of the Great Plains are the Native American tribes and First Nations peoples who have historically lived on the Interior Plains (the Great Plains) of North America. While hunting-farming cultures have lived on the Great Plains for centuries prior to European contact, the region is known for the horse cultures that flourished from the 17th century through the late 19th century. Their historic nomadism and armed resistance to domination by the government and military forces of Canada and the United States have made the Plains Indian culture groups an archetype in literature and art for Native Americans everywhere.

The Plains tribes are usually divided into two broad classifications which overlap to some degree. The first group became a fully nomadic horse culture during the 18th and 19th centuries, following the vast herds of American bison, although some tribes occasionally engaged in agriculture. These include the Arapaho, Assiniboine, Blackfoot, Cheyenne, Comanche, Crow, Gros Ventre, Kiowa, Lakota, Lipan, Plains Apache (or Kiowa Apache), Plains Cree, Plains Ojibwe, Sarsi, Nakoda (Stoney), and Tonkawa. The second group were sedentary and semi-sedentary, and, in addition to hunting bison, they lived in villages, raised crops, and actively traded with other tribes. These include the Arikara, Hidatsa, Iowa, Kaw (or Kansa), Kitsai, Mandan, Missouria, Omaha, Osage, Otoe, Pawnee, Ponca, Quapaw, Wichita, and the Santee Dakota, Yanktonai and Yankton Dakota.

The earliest people of the Great Plains mixed hunting and gathering wild plants. The cultures developed horticulture, then agriculture, as they settled in sedentary villages and towns. Maize, originally from Mesoamerica and spread north from the Southwest, became widespread in the south of the Great Plains around 700 CE.

Numerous Plains peoples hunted the American bison (or buffalo) to make items used in everyday life, such as food, cups, decorations, crafting tools, knives, and clothing. The tribes followed the seasonal grazing and migration of the bison. The Plains Indians lived in tipis because they were easily disassembled and allowed the nomadic life of following game.

The Spanish explorer Francisco Vásquez de Coronado was the first European to describe the Plains Indian culture. He encountered villages and cities of the Plains village cultures. While searching for a reputedly wealthy land called Quivira in 1541, Coronado came across the Querechos in the Texas panhandle. The Querechos were the people later called Apache. According to the Spaniards, the Querechos lived "in tents made of the tanned skins of the cows (bison). They dry the flesh in the sun, cutting it thin like a leaf, and when dry they grind it like meal to keep it and make a sort of sea soup of it to eat. ... They season it with fat, which they always try to secure when they kill a cow. They empty a large gut and fill it with blood, and carry this around the neck to drink when they are thirsty." Coronado described many common features of Plains Indians culture: skin tepees, travois pulled by dogs, Plains Indian Sign Language, and staple foods such as jerky and pemmican.

Siouan language speakers may have originated in the lower Mississippi River region. They were agriculturalists and may have been part of the Mound Builder civilization during the 9th–12th centuries. Wars with the Ojibwe and Cree peoples pushed the Lakota (Teton Sioux) west onto the Great Plains in the mid- to late 17th century. The Shoshone originated in the western Great Basin and spread north and east into present-day Idaho and Wyoming. By 1500, some Eastern Shoshone had crossed the Rocky Mountains into the Great Plains. After 1750, warfare and pressure from the Blackfoot, Crow, Lakota, Cheyenne, and Arapaho pushed Eastern Shoshone south and westward. Some of them migrated as far south as Texas, emerging as the Comanche by 1700.

European explorers and hunters (and later, settlers) brought diseases against which the Indians had no resistance. Between a half and two-thirds of the Plains Indians are thought to have died of smallpox by the time of the Louisiana Purchase. The 1837 Great Plains smallpox epidemic spread across the Great Plains, killing many thousands between 1837 and 1840. In the end, it is estimated that two-thirds of the Blackfoot population died, along with half of the Assiniboines and Arikaras, a third of the Crows, and a quarter of the Pawnees.

The Plains Indians historically lived without horses, which went extinct in the Americas 15,000–13,000 years ago. However, the reintroduction of the horse in the 16th century had a profound impact on the culture of the Great Plains. When horses were obtained, the Plains tribes rapidly integrated them into their daily lives. People in the southwest began to acquire horses in the 16th century by trading or stealing them from Spanish colonists in New Mexico. As horse culture moved northward, the Comanche were among the first to commit to a fully mounted nomadic lifestyle. This occurred by the 1730s, when they had acquired enough horses to put all their people on horseback.