Ethyl tert-butyl ether is a high-octane gasoline blending component with excellent performance and has important industrial application value. When ethanol and isobutylene react to form ethyl tertiary butyl ether, there is an azeotrope system of ethyl tertiary butyl ether and ethanol. The efficient production of ethyl tert-butyl ether and the precise separation of the ethyl tert-butyl ether/ethanol azeotrope are the keys to the entire process. In this work, reactive extractive distillation process and reactive extractive dividing-wall process were designed to achieve high-quality production and separation of ethyl tert-butyl ether. By analyzing the relative volatility of the solvents and combining molecular dynamics simulation and quantum chemical calculations, ethylene glycol was selected as the extractant for the separation of ethyl tert-butyl ether/ethanol. Based on the total annual cost as the objective function, three different ethyl tert-butyl ether production and separation processes were optimized and obtained the best process parameters. Finally, the whole process was analyzed from the aspects of economy, environment and exergy loss efficiency. Compared with common process, the total annual cost of reactive extractive dividing-wall process was reduced by 14.56%. The global warming potential, acidification potential and abiotic depletion potential of the reactive extractive dividing-wall process were 28.38%, 29.03%, and 28.36% lower than those of common process respectively. The exergy loss efficiency of reactive extractive dividing-wall process was reduced by 10.9%. The results showed that reactive extractive dividing-wall process has obvious economic advantages and environmental benefits and the actual production of ethyl tert-butyl ether and the separation of ethyl tert-butyl ether/ethanol azeotrope system have certain guiding significance.