The concepts of green process engineering and rigorous model-based approaches have proven to be highly beneficial in process engineering. Although a combination of these two principles thus appears extremely promising, it is not found very commonly in literature. The very high complexity resulting from this combination poses great challenges for the process design and design engineers. Therefore, this work presents an innovative methodology for the model-based process design with superimposed multi-objective optimization for an exemplary process. This process for the enzymatic hydrolysis of fatty acid methyl ester combines several aspects of green process engineering and represents an exemplary process with an enzymatic liquid-liquid-solid reaction system. The optimization results based on operating and investment costs reveal important insights on the exemplary process and highlight the great advantages of the developed methodology as a profound basis for academic and industrial process design purposes. (c) 2017 American Institute of Chemical Engineers AIChE J, 63: 1974-1988, 2017