Iron sulfide (FeS) is a promising material for separating copper and arsenic from strongly acidic wastewater due to its S2− slow-release effect. However, uncertainties arise because of the constant changes in wastewater composition, affecting the selection of operating parameters and FeS types. In this study, the aging method was first used to prepare various controllable FeS nanoparticles to weaken the arsenic removal ability without affecting the copper removal. Orthogonal experiments were conducted, and the results identified the Cu/As ratio, H2SO4 concentration, and FeS dosage as the three main factors influencing the separation efficiency. The backpropagation artificial neural network (BP-ANN) model was established to determine the relationship between the influencing factors and the separation efficiency. The correlation coefficient (R) of overall model was 0.9923 after optimizing using genetic algorithm (GA). The BP-GA model was also solved using GA under specific constraints, predicting the best solution for the separation process in real-time. The predicted results show that the high temperature and long aging time of FeS were necessary to gain high separation efficiency, and the maximum separation factor can reached 1,400. This study provides a suitable sulfurizing material and a set of methods and models with robust flexibility that can successfully predict the separation efficiency of copper and arsenic from highly acidic environments.