To optimize and evaluate the hydrodynamic performance and gas exchange efficiency of a newly developed centrifugal blood pump and membrane oxygenator for extracorporeal membrane oxygenation (ECMO) support, blood pump and oxygenator designs were optimized from a hydrodynamic perspective by adopting a five-blade impeller for the pump and a circular flow path with a central inlet and bottom outlet for the oxygenator. Computational fluid dynamics (CFD) was used to evaluate shear distribution. In vitro experiments assessed pressure-flow characteristics. Long-term ECMO support (14 days) was performed in sheep using both venovenous (VV) and venoarterial (VA) modes. Key parameters, including plasma-free hemoglobin and comprehensive blood tests (biochemistry, coagulation, platelet function), were analyzed. Computational fluid dynamics revealed uniform pump flow with minimal high-shear volume and negligible stagnation in the oxygenator, indicating low hemolysis and thrombosis risk. In vitro, the oxygenator showed lower transmembrane pressure than Quadrox-PLS across 1–7 L/min and higher O₂ transfer (1–3 L/min). In vivo, circuit flow was stable (2.2 L/min [VV], 2.5 L/min [VA]) and oxygenator ΔP remained 10–12 mm Hg with stable oxygen exchange (155 ml/min [VV], 165 ml/min [VA]), and plasma-free hemoglobin (pfHb) remained below 50 mg/dL. Three non–device-related deaths occurred, and there were no device-related thrombotic or hemorrhagic complications. The ECMO system demonstrated excellent mechanical stability, effective long-term oxygenation, favorable hemodynamic performance, and outstanding hemocompatibility in large-animal models.