The Great American Desert was an inaccurate term that described the area west of the Missouri River and east of the Rocky Mountains in the 19th century.

This area is actually mostly semi-arid grassland and is now extensively cultivated for agriculture. But in the 19th century, the area was relatively unexplored and the belief was that the area was almost uninhabitable. When the region was purchased by the United States as part of the Louisiana Purchase in 1803, President Jefferson wrote of the "immense and trackless deserts" of the region. In 1823, Stephen Long, a government surveyor, produced a map labelling the area the Great American Desert and the name persisted. Even people with direct experience of the region who were able to observe the area was not a desert assumed the contradictory conditions they saw were temporary or localized.

Belief in the existence of the desert affected the development of the United States. Settlers heading westward often attempted to pass through the region as quickly as possible enroute to what was regarded as better land farther west. The area was also considered as a useful region for the resettlement of American Indians who were being forcibly removed from the eastern United States. Railroad interests seeking right of ways through the region also benefited from the belief that the land was commercially valueless.

By the mid-19th century, people had begun settling in the region despite its poor reputation. The local inhabitants came to realize the area was in fact well suited for farming. Experts of the era proposed theories that maintained the earlier reports had been accurate and the climate had changed. Some even credited the settlers themselves as having caused the change by planting crops and trees. The slogan "rain follows the plow" was created to describe this belief.

The area once called Great American Desert is now more accurately named the Great Plains. The original term is now sometimes used to describe the arid region of the Southwest, which includes parts of northern Mexico and the four deserts of North America.