The Mississippi River Basin is a vast near-planar surface, an area upon which sunlight falls and wind flows. Its gently banked geomorphology channels precipitation, sediment, biota, and human activity into a dynamic locus of regional Earth system interactions. This paper describes the major features of this region’s energy exchanges from a thermodynamic Earth systems perspective. This analysis is combined with descriptions of the historical and socio-political contexts that have helped shape energy use. In doing so, the paper contrasts the region’s available energy exchanges and flows with their anthropogenic diversion, providing an account of human impact at a regional scale. It also offers theoretical estimates of the potential availabilities of renewable energy. This is contrasted with a description of the geological formation of stocks of fossil energy in the region. On these bases, a number of maps are presented and an assessment of the region’s energy flows is offered. These exercises point to significant affordances for achieving regional de-fossilisation at the river basin scale.