The complex non-linear behavior presented in the biological treatment of wastewater requires an accurate model to predict the system performance. This study evaluates the effectiveness of an artificial intelligence (AI) model, based on the combination of artificial neural networks (ANNs) and genetic algorithms (GAs), to find the optimum performance of an up-flow anaerobic sludge blanket reactor (UASB) for saline wastewater treatment. Chemical oxygen demand (COD) removal was predicted using conductivity, organic loading rate (OLR) and temperature as input variables. The ANN model was built from experimental data and performance was assessed through the maximum mean absolute percentage error (= 9.226%) computed from the measured and model predicted values of the COD. Accordingly, the ANN model was used as a fitness function in a GA to find the best operational condition. In the worst case scenario (low energy requirements, high OLR usage and high salinity) this model guaranteed COD removal efficiency values above 70%. This result is consistent and was validated experimentally, confirming that this ANN-GA model can be used as a tool to achieve the best performance of a UASB reactor with the minimum requirement of energy for saline wastewater treatment.