Abstract The membrane oxygenator is an essential component in the Extracorporeal Membrane Oxygenation (ECMO) system to offer temporary support to the respiratory system. This study aims to optimize the hemodynamic performance and reduce the thrombosis risk of a membrane oxygenator prototype using computational fluid dynamics. Numerical simulations of steady laminar flow in a full-scale oxygenator prototype (model 1) and two optimized structure Models 2 and 3 at flow rates of 5∼7L/min are carried out using the porous media model. Flow-field-based hydraulic performance indicators and the thrombus risk indicator of the three models are compared extensively. Detailed internal flow analysis revealed that adverse flow states such as insufficient flow circulation in the inlet shunt cone zone, large flow separations at the top corners of heat exchangers, and intensive flow impingement at the exit elbow tube are notably improved in the optimized model 2 and 3. The improvement is more significant at high flow rates. Performance parameters quantitatively validate the effect of optimized configurations. Specifically, at a flow rate of 7L/min, the flow uniformity indexes for the original model at the shunt cone exit increase from 0.884 to 0.923 and 0.890 in the two modified models. The total pressure loss is reduced by over 14%, and maximum wall shear stress is notably reduced from 241.46Pa to 135.9Pa. Additionally, the optimized models exhibited lower thrombus risk. The optimized designs emphasize the importance of smooth transitions between cross-sections and minimizing abrupt changes in flow direction. The employment of flow-field-based parameters allows for the establishment of the relationship between geometric and performance parameters to guide effective design optimization and ensure the safe clinical operation of oxygenator prototypes.