[en] Highlights: • Orthogonal method is utilized to optimize the configurations of fuel cell stack. • Effects of configurations and operating parameters are numerically investigated. • Operating parameters affect power density and system efficiency in different way. • Counter-flow of both hydrogen and coolant can improve water and thermal managements. -- Abstract: Water and thermal managements are critical for the performance and operation stability of proton exchange membrane fuel cell (PEMFC) stacks, which are highly associated with the stack configurations and cathode operating parameters that need to be well optimized. In this work, a numerical study is conducted with orthogonal analysis method to investigate the effect of stack configurations and cathode operating parameters on stack performance including power density, system efficiency and stack uniformity. An orthogonal array (OA) with three levels and six factors is designed to determine the interaction of each parameter as well as the optimal combination of configurations and operating parameters. The results indicate that the optimal combination with respect to power density and system efficiency is not consistent due to the associated parasitic loads. Moreover, counter-flow configuration of hydrogen channel is able to improve the water management and counter-flow configuration of coolant channel is beneficial for thermal management, both of which can further improve the stack uniformity that is desired in real application.