Cotton is one of the important crops that play an important role in creating a livelihood for rural people in many parts of Iran. Cotton production necessitates a large amount of resources (e.g., fossil energy and agrochemicals, all of which have the potential to damage the environment in various ways). The purpose of the current study was to evaluate the environmental effects of cotton production in the South Khorasan Province of Iran. For this purpose, life cycle assessment (LCA) and data envelopment analysis (DEA) techniques have been applied to investigate the environmental impacts of cotton production. LCA is a practical method to evaluate the environment on the product flow, in which all aspects of the product life cycle are examined by a comprehensive approach. Furthermore, combining the LCA method with other managerial strategies such as DEA could allow researchers to provide decision-makers with more practical and interpretable data. The findings of the efficiency test showed that the average technical efficiency, pure technical efficiency, and scale efficiency were 0.81, 0.92, and 0.87, respectively. Respiratory inorganics (i.e., respiratory effects resulting from winter smog caused by emissions of dust, sulfur, and nitrogen oxides to air) posed the greatest environmental burden in cotton production, followed by non-renewable energy, carcinogens, and global warming. In addition, the highest effects were on human health, and then, on resources and climate change. Energy, on-system pollution, and waste played a crucial role in the environmental impacts of cotton processing. This study suggests improving farmers' knowledge toward the optimum application of chemical fertilizers, or their substitution with green fertilizers, which reduces the environmental effect of growing cotton in the area.