Cardiopulmonary bypass (CPB) and veno-arterial extracorporeal membrane oxygenation are critical tools in contemporary cardiac surgery and intensive care, respectively. While these techniques share similar components, their application contexts differ, leading to distinct immune dysfunctions which could explain the higher incidence of nosocomial infections among ECMO patients compared to those undergoing CPB. This review explores the immune modifications induced by these techniques, comparing their similarities and differences, and discussing potential treatments to restore immune function and prevent infections. The immune response to CPB and ECMO involves both humoral and cellular components. The kinin system, complement system, and coagulation cascade are rapidly activated upon blood contact with the circuit surfaces, leading to the release of pro-inflammatory mediators. Ischemia–reperfusion injury and the release of damage-associated molecular patterns further exacerbate the inflammatory response. Cellular responses involve platelets, neutrophils, monocytes, dendritic cells, B and T lymphocytes, and myeloid-derived suppressor cells, all of which undergo phenotypic and functional alterations, contributing to immunoparesis. Strategies to mitigate immune dysfunctions include reducing the inflammatory response during CPB/ECMO and enhancing immune functions. Approaches such as off-pump surgery, corticosteroids, complement inhibitors, leukocyte-depleting filters, and mechanical ventilation during CPB have shown varying degrees of success in clinical trials. Immunonutrition, particularly arginine supplementation, has also been explored with mixed results. These strategies aim to balance the inflammatory response and support immune function, potentially reducing infection rates and improving outcomes. In conclusion, both CPB and ECMO trigger significant immune alterations that increase susceptibility to nosocomial infections. Addressing these immune dysfunctions through targeted interventions is essential to improving patient outcomes in cardiac surgery and critical care settings. Future research should focus on refining these strategies and developing new approaches to better manage the immune response in patients undergoing CPB and ECMO.