Acetonitrile is an important and widely used organic solvent, but its production is limited by its production process. In this study, a new process for the amination of ethanol to acetonitrile was developed. On the basis of the reaction kinetics, the operating conditions of reaction temperature and raw material ratio were optimized. Comprehensive economic, thermodynamic, and environmental analyses were used to improve the production performance and energy utilization. Thermodynamic analysis of the acetonitrile production process shows that the separation and purification unit and product refining unit make the most critical contributions to exergy loss. The introduction of heat integration technology can effectively recover process energy and reduce the energy consumption of the whole process. On the basis of the highest product yield, the total annual cost was 6.34 x 10(6) $/year. The exergy efficiency of the amination process to convert ethanol to acetonitrile was 56%, which could be thermodynamically improved. Environmental analysis showed that the reaction synthesis unit had a greater environmental effect than the other two studied units. A new method combining process simulation, economics, thermodynamics, and environmental performance analysis is proposed to improve the energy efficiency and quality of the acetonitrile production process.