Uniformity of fluid distribution in the manifold is extremely essential to enhance the output performance and prolong the lifetime of high power proton exchange membrane (PEM) fuel cell stack. The entrance effects are usually ignored in the existing studies focusing on the fluid distribution at stack level, which cannot thoroughly guide the high-power fuel cell stack development. In this study, the effects of entrance geometry on the fluid distribution in manifold for a high-power fuel cell stack are investigated using computational fluid dynamics (CFD) method. Optimizations of the intermediate zone configuration in upper endplate and inlet tube diameter are conducted under different current densities. Results show that the fluid distribution in manifold is strongly influenced by entrance geometry which determines the generation of vortexes. The mass flow rates in unit cells near the entrance of the stack with diffuser-type intermediate zone are enhanced compared to the non-diffuser-type intermediate zone. The coefficient of variation (CV) of mass flow rate decreases dramatically as the ratio of inlet tube to manifold hydraulic diameter (RITMHD) increases and then raises. The experimental and simulation results are useful in guiding the design of high-power PEM fuel cell stacks to seek higher power density.