Hydrogen has emerged as a therapeutic agent in inflammatory critical illnesses due to its potential to modulate inflammation and oxidative stress. However, its role in extracorporeal membrane oxygenation (ECMO), a life-saving intervention for severe cardiorespiratory failure associated with pronounced inflammation and oxidative stress, remains largely unexplored. This ex vivo study investigated whether ECMO could serve as an effective vehicle for hydrogen delivery. It also evaluated hydrogen’s effects on oxidative stress, inflammation, and coagulation responses arising from the interaction between human blood and non-biological ECMO surfaces. Four healthy male volunteers each provided two blood donations, 6 months apart. We assigned human blood-filled ECMO circuits to two different sweep gas formulations: a CO₂-enriched gas mixture (n = 4) or a mixture of 2% hydrogen in CO₂-enriched gas (n = 4). At T0, stable hydrogen concentrations (9.82 ± 1.97 μmol/L) were achieved and maintained for 6 hours, confirming the reliability of the hydrogen delivery method. Hydrogen exposure significantly reduced collagen (p = 0.01), TRAP-6 (p = 0.04), and ADP-induced (p = 0.04) platelet aggregation and showed a trend toward reduction in oxidative stress markers. In conclusion, this preliminary ex vivo study demonstrates the feasibility of delivering hydrogen gas via the sweep gas of a clinically established ECMO machine and its initial effects on blood, warranting further investigation in larger preclinical animal models.