Process optimization using a physical process or its comprehensive model often requires a significant amount of time. To remedy this problem, metamodels, or surrogate models, can be used. In this investigation, a methodology for optimizing the biobutanol production process via the integrated acetone-butanol-ethanol (ABE) fermentation-membrane pervaporation process is proposed. In this investigation, artificial neural networks (ANNs) were used as metamodels in an attempt to reduce the time needed to circumscribe the Pareto domain and identify the best optimal operating conditions. Two different metamodels were derived from a small set of operating conditions obtained from a uniform experimental design. The first series of metamodels were derived to entirely replace the phenomenological model of the butanol fermentation process by representing the relationship that exists between five operating conditions and four performance criteria. The second series of metamodels were derived to estimate the initial concentrations under steady-state conditions for the eight chemical species within the fermenter in order to expedite convergence of the process simulator. The first series of metamodels led to an accurate Pareto domain and reduced the computation time to circumscribe the Pareto domain by a factor of 2500. The second series of metamodels led to only a small reduction of computation time (a factor of approximately 2) because of the inherently slow convergence of the overall fermentation process.