Cotton production is the number one crop enterprise in Georgia in terms of revenue generation. However, due to continuous deterioration of soil quality with conventional tillage and chemical fertilizer application, the economic viability and sustainability of cotton production in Georgia are questionable. Residue management systems (RMSs) comprising winter cover crops were analyzed as an alternative to the existing system, which consists of conventional tillage and chemical fertilizer using yield benefit, net revenue, carbon sequestration, and yield efficiency criteria. Four different RMSs were examined for profitability and input efficiency. Four RMSs encompassing tillage versus no-till and chemical versus organic sources of plant nutrients were compared for their yield and net return differences. No-till and poultry litter with a cover crop was the only system with a positive return and crop yield based on the results from experimental data. Limited results from the experimental field were reinforced using a simulation study. When cotton yield is simulated with an alternative level of organic matter and nitrogen application, production function shows efficiency in input application at the higher level of organic matter. Regression results based on an erosion productivity impact calculator/environmental policy integrated climate (EPIC) simulation indicated that, in the long term, a no-till and poultry litter system may have promise in the region. The results from simulation confirm the results from the experimental study. This study reflected a need to change the cotton management system from the 200-year-old practice of employing intensively cultivated conventional tillage and chemical fertilizers to a new renewable resource-based system where residue management and organic sources of nutrients would be the key components.