We present a case of successfully treating an adult woman with a lethal bupropion overdose with VA-ECMO. The patient presented to the hospital with severe encephalopathy, which progressed to seizures and cardiac arrest shortly after arrival. This was preceded by ingesting numerous tablets of 300 mg extended-release bupropion. Her bupropion level was 946 ng/dL (therapeutic level 10–100 ng/dL). The patient’s clinical presentation was compounded by severe neurological failure that met the clinical brain death criterion. Despite high-dose catecholamines, the patient remained in refractory shock. An echocardiogram demonstrated severe biventricular failure with a left ventricular ejection fraction (LVEF) of under 10%. VA-ECMO support was initiated, and the patient was retrieved to our ECMO center, where a percutaneous left-ventricular assist device (LVAD) was further placed. Her cardiovascular status slowly improved, with catecholamine support significantly weaned down by hospital day (HOD) 6. The patient was removed from VA-ECMO and LVAD on HOD 8 and 10, respectively. A subsequent echocardiogram showed an LVEF of 45%. The patient’s neurological recovery lagged, with only a weak gag reflex on HOD 8; however, by HOD 10, she intermittently regained consciousness. By HOD 13, although weak and requiring mechanical ventilation, the patient could stay awake and express her needs effectively. On HOD 34, the patient was discharged with intact neurological and cardiopulmonary function. Severe bupropion overdose can cause refractory shock and apparent brain death, as seen in the patient. In this case, extracorporeal life support was vital in bridging detoxification and recovery.