Extracorporeal circulation (ECC) procedures, such as cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), take over the function of one or more organs, providing clinicians time to treat underlying pathophysiological conditions. ECMO and CPB carry significant mortality rates for patients, despite prior decades of research focused on the resulting failure of critical organs. Since the focus of these procedures is to support blood flow and provide oxygen-rich blood to tissues, a shift in research toward the effects of ECMO and CPB on the microcirculation is warranted. Along with provoking systemic responses, both procedures disrupt the integrity of red blood cells, causing release of hemoglobin (Hb) from excessive foreign surface contact and mechanical stresses. The effects of hemolysis are especially pronounced in the microcirculation, where plasma Hb leads to nitric oxide scavenging, oxidization, formation of reactive oxygen species, and inflammatory responses. A limited number of studies have investigated the implications of ECMO in the microcirculation, but more work is needed to minimize ECMO-induced reduction of microcirculatory perfusion and consequently oxygenation. The following review presents existing information on the implications of ECMO and CPB on microvascular function and proposes future studies to understand and leverage key mechanisms to improve patient outcomes.