The uses of native plants of the Great Plains for food, medicine, and utilitarian purposes were many and of profound importance to the Native Americans. Plant lore has declined dramatically since European American settlement, and the majority of foods and virtually all medicines today are imported into the region.

The Great Plains has more than 3,000 plant species. All Native American tribes of the region used numerous plant species, totaling in the hundreds. Most of the knowledge of their uses for food, medicine, and utilitarian purposes was held in oral histories, and many Native American uses continue today on Plains reservations. Anthropologists and ethnobotanists have recorded much information on the topic. Not surprisingly, most plants utilized were prairie plants, although some trees and shrubs also had important uses.

More native prairie plants (over 200) have been documented as being used by Plains Indians for medicine than for any other use. Some, such as yarrow (Achillea millefolium) and the purple coneflower (Echinacea angustifolia), were widely used for their general medicinal qualities. Others, such as locoweed (Astragalus), with its toxic amounts of alkaloids and selenium, were used more successfully to treat both internal and external maladies. Most people knew the many common uses of plants, but there were also highly trained individuals, medicine men and medicine women, who had very specific knowledge about plants and used them in spiritual ceremonies for healing.

In most cases, the belief system was that the spirit healed the individual, and that the plant was a vehicle for this process. The major medicinal plant cures of Plains Indian tribes have plausible scientific explanations for their use and effectiveness. Most of them contain active medicinal constituents. It is extraordinary that many of these uses were discovered. Certainly, much learning occurred through trial and error, but Native Americans also believed that knowledge could be gained through dreams and visions, and plant lore was of course handed down, orally, over generations. In fact, the healing systems of Native Americans are ancient and suggest links to Asia. For example, the Pawnees burned the stems of yarrow and leadplant (Amorpha canescens) as short punks placed on rheumatic points to relieve pain, a practice known as "moxabustion," which today is almost completely associated with Asian medicine. Only a very few medicinal plants used by Native Americans were adopted by European American immigrants, primarily because the traditions were vastly different and few European Americans were willing to give credence to Native American learning. One that was adopted was the purple coneflower, which has been imported into Europe and more recently been made available commercially in the United States as an immune system stimulant, used primarily to ward off colds.

Food uses of native plants were vitally important to the Great Plains Indians, and played an essential dietary role. More than 120 native prairie plants were used for food. Many plants were used for seasoning, flavors, tea, or nutritional needs (greens in the spring were used to ward off scurvy). The most important native food plant was the prairie turnip (Psoralea esculenta). This starchy, leguminous root was eaten as a staple or added to bison stew. It was also dried and traded or stored. The prairie turnip was so important to the Omahas that they determined the route of their summer buffalo hunt in the High Plains by the locations where the women could find the plant. Since wild food procurement was primarily women's work, little of this knowledge was passed on to European immigrants because interaction between Native American women and women settlers rarely occurred.

Native Americans had many other uses for wild plants, such as cattails and rushes for mats, white sage (Artemisia ludoviciana) and eastern redcedar (Juniperus virginiana) for ceremonial incense, and trees for lodges and firewood. Of course, Native American women had long cultivated corn, beans, squash, sunflowers, and other crops. With European American settlement, large numbers of new cultivars were introduced for farming and gardening, but the diversity and variety have dramatically decreased over the decades, and farmers now only grow a handful of crops (and indeed only a few genetic varieties of a small number of crops). Only a small number of the native plants originally used by Plains Indians –wild plums (Prunus americana), chokecherries (Prunus virginiana), wild grapes (Vitis riparia), and other–are now used for jams, jellies, and wine by the wider population.