This study focuses on the causes and consequences of depopulation in the Lower Mississippi Valley during the Protohistoric period (ca. AD 1500-1700). The Protohistoric period in the region is characterized by indirect and infrequent contact between Europeans and Indigenous peoples. Nevertheless, dramatic population losses and/or regional abandonments accompanied the collapse, transformation, and coalescence of Native American societies during this period across the interior southeastern United States. The causes and timing of these phenomena, however, were often multiple and occurred in a time-transgressive manner. The goal of the research presented in this dissertation was the identification of the forces and processes of cultural and demographic change that were responsible for transformation experienced by a Late Mississippian population represented by the Tillar Complex in southeast Arkansas during the Protohistoric period. Multiple lines of evidence, including archaeological, historical and environmental data, were employed to test a multi-causal model of population decline, adaptation, and abandonment of Bayou Bartholomew by Tillar phase peoples sometime during the seventeenth century. The external forces hypothesized to have been catalysts that drove social and cultural transformations and eventual depopulation include the military expedition of Hernando De Soto, disease, and a series of prolonged droughts that impacted large areas of the Southeast in the sixteenth and seventeenth centuries.