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Abstract: An integrated multi-objective optimization approach within the framework of nonlinear regression-based kinetic modeling and desirability function was proposed to optimize an up-flow anaerobic sludge blanket (UASB) reactor treating poultry manure wastewater (PMW). Chen–Hashimoto and modified Stover–Kincannon models were applied to the UASB reactor for determination of bio-kinetic coefficients. A new empirical formulation of volumetric organic loading rate was derived for the first time for PMW to estimate the dimensionless kinetic parameter (K) in the Chen–Hashimoto model. Maximum substrate utilization rate constant and saturation constant were predicted as 11.83gCOD/L/day and 13.02gCOD/L/day, respectively, for the modified Stover–Kincannon model. Based on four process-related variables, three objective functions including a detailed bio-economic model were derived and optimized by using a LOQO/AMPL algorithm, with a maximum overall desirability of 0.896. The proposed optimization scheme demonstrated a useful tool for the UASB reactor to optimize several responses simultaneously. [Copyright &y& Elsevier]