The goal of this study is to develop a computational fluid dynamics (CFD) modeling approach to better estimate the blood flow dynamics in the bundles of the hollow fiber membrane based medical devices (i.e., blood oxygenators, artificial lungs, and hemodialyzers). Three representative types of arrays, square, diagonal, and random with the porosity value of 0.55, were studied. In addition, a 3D array with the same porosity was studied. The flow fields between the individual fibers in these arrays at selected Reynolds numbers (Re) were simulated with CFD modeling. Hemolysis is not significant in the fiber bundles but the platelet activation may be essential. For each type of array, the average wall shear stress is linearly proportional to the Re. For the same Re but different arrays, the average wall shear stress also exhibits a linear dependency on the pressure difference across arrays, while Darcy's law prescribes a power-law relationship, therefore, underestimating the shear stress level. For the same Re, the average wall shear stress of the diagonal array is approximately 3.1, 1.8, and 2.0 times larger than that of the square, random, and 3D arrays, respectively. A coefficient C is suggested to correlate the CFD predicted data with the analytical solution, and C is 1.16, 1.51, and 2.05 for the square, random, and diagonal arrays in this paper, respectively. It is worth noting that C is strongly dependent on the array geometrical properties, whereas it is weakly dependent on the flow field. Additionally, the 3D fiber bundle simulation results show that the three-dimensional effect is not negligible. Specifically, velocity and shear stress distribution can vary significantly along the fiber axial direction.