Platinum-group-metal-free (PGM-free) catalysts hold great potential to replace their expensive Platinum-based counterparts in proton exchange membrane fuel cells because of their exceptional catalytic activity, outstanding abundance, and low cost. However, inferior cell performance resulting from the ill catalyst layer design remains a critical barrier for their practical applications in fuel cells. Here, we present a refined two-phase model to reveal the effects of the design and operating parameters on the performance of the fuel cells. To accurately capture the cathodic process, key descriptors (site density, turnover frequency, and active site availability) of PGM-free catalysts are incorporated into the agglomerate model. Numerical results show that catalyst loading, porosity, and site density significantly affect cell performance. In contrast to the high catalyst loadings usually employed in the reported literature, we find that a moderate catalyst loading is beneficial for achieving the best cell performance due to the balanced activity, ohmic and concentration polarizations. Moreover, the optimal catalyst loading can be further reduced with higher site densities. Optimal porosity of the cathode catalyst layer also exists due to the contradiction between mass transport and effective electrochemical reaction rate in agglomerates. Additionally, our results show that PGM-free catalyst layer should be optimized accordingly when the fuel cells operate under H2-O2 and H2-air conditions. This work provides insightful understanding into the electrochemical reaction and mass transport behavior in the fuel cells with PGM-free catalysts, paving the way for the development of cost-effective and high-performance fuel cells.