Extracorporeal circulation (ECC) is frequently implemented in a vast array of modalities such as hemodialysis, cardiopulmonary bypass, extracorporeal membrane oxygenation (ECMO), and others. Patients receiving any such therapy are frequently encumbered with chronic inflammation, which is inherently accompanied by oxidative stress. However, ECC treatments themselves are also responsible for sustaining or promoting inflammation. On these grounds, an in vitro study was designed to investigate the therapeutic potential of molecular hydrogen (H₂) against pro-inflammatory agents in ECC settings. Five miniature ECMO circuits and a small vial (Control) were primed with heparinized blood from healthy adult donors (n = 7). Three of the ECMO systems were injected with lipopolysaccharide (LPS), out of which one was additionally treated with an H₂ gas mixture. After 6 h, samples were drawn for the assessment of specific biomarkers (MCP-1, MPO, MDA-a, TRX1, and IL-6). Preliminary results indicate a progressive oxidative and inflammatory response between the six systems. Circulation has triggered inflammation and blood trauma, but the staggering influence of LPS in this outcome is indisputable. Accordingly, hydrogen’s remedial potential becomes immediately apparent as biomarker concentrations tend to be lower in the H₂-handled circuit. Future research should have distinct objectives (e.g., dosage/duration/cycle of hydrogen administration) in order to ascertain the optimal protocol for patient treatment.