From the 16th through the 19th centuries

After 1492 European exploration of the Americas revolutionized how the Old and New Worlds perceived themselves. One of the first major contacts, in what would be called the American Deep South, occurred when conquistador Juan Ponce de León landed in La Florida in April of 1513. Ponce de León was later followed by other Spanish explorers, such as Pánfilo de Narváez in 1528 and Hernando de Soto in 1539.
Discovery of the Mississippi by William Henry Powell (1823–1879) is a Romantic depiction of de Soto seeing the Mississippi River for the first time. It hangs in the United States Capitol rotunda.

From the 16th through the 19th centuries, the population of Native Americans declined in the following ways: epidemic diseases brought from Europe; Genocide and warfare at the hands of European explorers and colonists; displacement from their lands; internal warfare, enslavement; and a high rate of intermarriage.

Most mainstream scholars believe that, among the various contributing factors, epidemic disease was the overwhelming cause of the population decline of the American natives because of their lack of immunity to new diseases brought from Europe.

With the rapid declines of some populations and continuing rivalries among their own nations, Native Americans sometimes re-organized to form new cultural groups