Septic shock, a global health concern, boasts high mortality rates. Research exploring the efficacy of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in septic shock remains limited. Our study aimed to establish a rodent model employing VA-ECMO in septic shock rats, assessing the therapeutic impact of VA-ECMO on septic shock. Nineteen Sprague-Dawley rats were randomly assigned to sham, septic shock, and (septic shock + VA-ECMO; SSE) groups. Septic shock was induced by intravenous lipopolysaccharides, confirmed by a mean arterial pressure drop to 25-30% of baseline. Rats in the SSE group received 2 hours of VA-ECMO support and 60 minutes of post-weaning ventilation. Sham and septic shock groups underwent mechanical ventilation for equivalent durations. Invasive mean arterial pressure monitoring, echocardiographic examinations, and blood gas analysis revealed the efficacy of VA-ECMO in restoring circulation and ensuring adequate tissue oxygenation in septic shock rats. Post-experiment pathology exhibited the potential of VA-ECMO in mitigating major organ injury. In summary, our study successfully established a stable septic shock rat model with the implementation of VA-ECMO, offering a valuable platform to explore molecular mechanisms underlying VA-ECMO's impact on septic shock.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.