Non-uniform flow in the hollow fiber membrane modules is believed to cause non-ideal performance of the module. To investigate the relationship between the module design and performance, a novel CFD model was developed to analyze numerically the effect of inlet manifold on the energy consumption and flow distribution for the module. The CFD results were compared with the experimental data and a good agreement between them was obtained. Eight manifolds were chosen as cases in the CFD simulation. The flow field in the shell and lumen sides and the flux distribution in the porous membrane zone were revealed by the CFD simulation. An adapted model has been proposed to account for the energy consumption distribution between the manifold and the fiber bundle. The manifold can consume a considerable portion of the overall energy with an improper structure design. When the fractional hole area of the inlet are 0.64%, 43.42%, and 100%, the proportion of the energy consumed by the manifold are 95%, 51%, and 7%, respectively. The non-uniform flow from the shell manifold to the module results in uneven velocity and pressure distributions in the shell side. However, the effect of the manifold structure on the flow distribution in the lumen side appears to be negligible. The flux distribution has a three-dimensional non-uniformity. The high velocity from the manifold opening to the module causes a high local flux at the beginning of the fiber, whereas the flow impingement on the dead end and the pressure drop in the lumen side results in a high local flux at the end of the fiber. The uniformity of the flux distribution depends on the flow distribution in the shell side with given fiber properties. For the specific hollow fiber membrane module in the present study, the inlet holes should be evenly distributed at the cross section to achieve uniform flow distribution in the module. To reduce the energy consumption, the fractional hole area should be as high as possible. The CFD model and the mechanism of how the inlet manifold affects the performance of the module will be beneficial to the structure design and optimization of the hollow fiber membrane modules.