Soil organic C sequestration can be a significant driver of how conservation management systems are adopted by producers and promoted by government agencies. Simulation of various tillage, crop rotation, and cover cropping conditions across the cotton growing region of the southeastern USA would allow us to assess whether soil type, climatic conditions, or management has the greatest control on soil organic C sequestration potential in the region. We estimated potential soil organic C sequestration under conventional and conservation management of cotton cropping systems in each county throughout the Cotton Belt using the recently calibrated soil conditioning index (SCI). Regional differences in production characteristics were also reflected in regional differences in SCI scores. Factors affecting SCI and soil organic C were: management > slope > precipitation > soil texture. The results of this study will be valuable to producers, extension agents, scientists, and policy makers in evaluating how the SCI performs under a diversity of environmental and management conditions throughout the southeastern USA.