<p>Global optimization of fuel cells is a key approach to enhance performance and extend lifespan. Furthermore, the response surface method can provide accurate predictive results with minimal data. This study utilizes the response surface method alongside a two-dimensional agglomerate model to perform numerical simulations of asymmetric proton exchange membrane fuel cells, focusing on thickness and operating parameters. The study analyzes the interactions among parameters and aims to identify optimal values for maximum power density. The structural and operational parameter optimization models have been developed, with average errors of 2.28% and 0.29%, respectively, leading to produce a predictive model with an average error of less than 3% ultimately. The optimized power density increased by 57.4%, with inlet pressure identified as the most influential factor. The asymmetric design enhances gas transport in the porous media region. Among the structural parameters, cathode thickness has a greater impact; while among the operating parameters, pressure exerts the greatest impact on cell performance. The optimal temperature ranges from 333 K to 343 K, with a noticeable marginal effect. Higher relative humidity can enhance power density, and it’s worth noting that cathode humidity is more sensitive to power density than anode humidity. A well-designed asymmetric configuration can enhance the water and thermal management of the fuel cell, leading to improved energy efficiency.</p>