Extracorporeal membrane oxygenation (ECMO) is the most important support for patients with severe cardiopulmonary failure. As the key component, the oxygenation membrane has suffered the risk of blood coagulation and plasma leakage in the long term. Herein, we prepare a sulfonate polyamide film on poly(ether sulfone) (PES) support via interfacial polymerization modulated by a sulfonate amine monomer. The pore diameter of the prepared polyamide film is ∼3.67 Å (exactly a little smaller than the water molecule, the base of plasma). By such size repulsion effect, the polyamide film demonstrates remarkable plasma leakage resistance (confirmed by human plasma circulation). Moreover, the introduction of the sulfonate amine monomer effectively enhances the anticoagulation performance (activated partial thromboplastin time (aPTT) prolongation >10 s). In addition, the PES support used for interfacial polymerization is modified and realizes improved porosity, hydrophilicity, and positive charge potential, resulting in lower mass transfer resistance and improved interfacial strength between the support and polyamide film. ECMO-simulated circulation tests prove the facilitation effect on gas exchange derived from the support modification and interfacial polymerization modulation. This work provides a composite membrane simultaneously with significant plasma leakage resistance and anticoagulation properties for efficient blood oxygenation.