The application of methodologies for the optimal design of integrated processes has seen increased interest in literature. This article builds on previous works and applies a systematic methodology to an integrated first and second generation ethanol production plant with power cogeneration. The methodology breaks into process simulation, heat integration, thermo-economic evaluation, exergy efficiency vs. capital costs, multi-variable, evolutionary optimization, and process selection via profitability maximization. Optimization generated Pareto solutions with exergy efficiency ranging between 39.2% and 44.4% and capital costs from 210 M$ to 390 M$. The Net Present Value was positive for only two scenarios and for low efficiency, low hydrolysis points. The minimum cellulosic ethanol selling price was sought to obtain a maximum NPV of zero for high efficiency, high hydrolysis alternatives. The obtained optimal configuration presented maximum exergy efficiency, hydrolyzed bagasse fraction, capital costs and ethanol production rate, and minimum cooling water consumption and power production rate.