Extracorporeal membrane oxygenation (ECMO) is a vital therapy for patients with severe cardiac and pulmonary failure. Despite technological advances, oxygenator dysfunction remains common, yet comparative clinical data across devices are limited. This study evaluated the performance of four contemporary adult oxygenators used in ECMO in a clinical, real-world setting. This retrospective single-center study included adult patients who received venovenous (VV) or venoarterial (VA) ECMO between January 2020 and December 2023 (N = 282). Oxygenators evaluated included the Medtronic Nautilus/Nautilus Smart, Getinge Heart Lung Support Module Advanced 7.0, Getinge Quadrox-iD Adult, and Fresenius X-Lung. Analyses were performed using propensity weighting and included adjustments for Acute Physiology and Chronic Health Evaluation II severity scores and baseline Charlson Comorbidity Index (CCI). No statistically significant differences in oxygen transfer across the membrane lung (VO₂) were observed among oxygenator types after adjustment for covariates. VO₂ declined over time during support (p < 0.001) and was higher in VV than VA ECMO mode (p = 0.002). Higher CCI was associated with lower VO₂ (p = 0.046). Finally, coagulation and hemolysis markers were comparable across all devices. Current-generation oxygenators provide similar gas exchange efficiency and hemocompatibility in clinical practice. Future prospective and multicenter studies incorporating direct measurements of gas transfer may further clarify device-specific characteristics and their impact on clinical outcomes.