In this paper, the design of experiments by the Taguchi method integrated with computational fluid dynamics simulation has been implemented for determining optimum operating conditions. A numerical model has been made with ANSYS code for proton exchange membrane fuel cell with the dead-end anode mode. This study assesses the impact of four factors, namely gas diffusion layer porosity, hydrogen mass fraction, nitrogen mass fraction, and water saturation. The influence of inlet pressure (Pin,1 = 104Pa, Pin,2 = 3.104Pa, and Pin,3 = 6.104Pa) and relative humidity (RH1 = 0%, RH2 = 50%, and RH3 = 100%) have been studied using the integrative approach. For Pin,1, Pin,2, and Pin,3, the optimum levels yielding a superior performance were (L5, L3, L2, and L1), (L5, L3, L2, and L2), and (L5, L3, L3, and L1), respectively. For RH1, RH2, and RH3, the optimum levels yielding a better performance were (L5, L1, L3, and L1), (L5, L3, L1, and L1), and (L5, L3, L2, and L1), respectively. Our findings revealed that the electrical current density reflecting the cell performance decreased with increasing the water accumulation, the nitrogen mass fraction, and decreasing the hydrogen mass fraction. The percentage error between Taguchi calculations and computational outputs of power densities was 0.23%, 0.19%, 0.45%, 0.28%, 0.2%, and 0.16%.