At Joara, near Morganton, North Carolina, Native Americans of the Mississippian culture interacted with Spanish explorers of the Juan Pardo expedition, who built a base there in 1567 called Fort San Juan. Expedition documentation and archaeological evidence of the fort and Native American culture both exist. The soldiers were at the fort about 18 months (1567-1568) before the natives killed them and destroyed the fort. (They killed soldiers stationed at five other forts as well; only one man of 120 survived.) Sixteenth-century Spanish artefacts have been recovered from the site, marking the first European colonization in the interior of what became the United States.
Scholars have searched the records of Hernando de Soto in 1539–1543 looking for evidence of contacts with Mississippians. He visited many villages, in some cases staying for a month or longer (see here). Some encounters were violent, while others were relatively peaceable. In some cases, De Soto seems to have been used as a tool or ally in long-standing native feuds. In one example, de Soto negotiated a truce between the Pacaha and the Casqui.
De Soto’s later encounters left about half of the Spaniards and perhaps many hundreds of Native Americans dead. The chronicles of de Soto are among the first documents written about Mississippian peoples, and are an invaluable source of information on their cultural practices. The chronicles of the Narvaez Expedition was written before the de Soto expedition; in fact, it was the Narvaez expedition that informed the Court of de Soto about the New World.
After the destruction and flight of the de Soto expedition, the Mississippian peoples continued their way of life with little direct European influence. Indirectly, however, European introductions would change the face of the Eastern United States. Diseases such as measles and smallpox caused so many fatalities, because the natives lacked immunity, that they undermined the social order of many chiefdoms. Some groups adopted European horses and changed back to nomadism (Bense pp. 256–257, 275–279). Political structures collapsed in many places. By the time more documentary evidence was being written, the Mississippian way of life had changed irrevocably. Some groups maintained an oral tradition link to their mound-building past (such as the late 19th-century Cherokee- Hudson pp. 334). Other Native American groups, having migrated many hundreds of miles and lost their elders to diseases, did not know their ancestors had built the mounds dotting the landscape. This contributed to the “Myth of the Mound Builders” as a people distinct from Native Americans, which was officially debunked by Cyrus Thomas in 1894.