Abstract: This study targets the setpoint optimization of some controlled variables in a wastewater treatment process. First, an improved differential evolution algorithm is proposed and its performance is verified by the simulations on four benchmark functions. Then, the effluent quality, aerating energy consumption, pumping energy consumption and sludge treatment payment are combined into a single optimization target. Next, the setpoints of the controlled variables are solved by the proposed IDE algorithm. Finally, four different control strategies of a wastewater treatment process under three different weather influents are evaluated. The simulation results show that the optimized control systems result in a decrease of operating costs, a shortened time length above the discharge limit of key effluent variables, and an improvement of the effluent quality when compared with other control strategies.