Calcium-channel blocker overdose can result in profound vasoplegia and cardiogenic shock, which can quickly spiral into multi-organ failure and death. In this case report, we discuss two separate cases of massive amlodipine overdose with polydrug intoxication (Patient A: amlodipine and quetiapine; Patient B: amlodipine, fluoxetine and zopiclone), both of which were complicated by life-threatening vasoplegic shock refractory to supportive therapy (endotracheal intubation, fluid resuscitation, activated charcoal, vasopressors and inotropes), multimodal antidotes (calcium and hyper-insulinemic euglycemic therapy) and even second-line treatment (methylene blue and therapeutic plasma exchange). Despite exhausting all therapeutic options, resuscitation remained futile with no clinical response elicited until veno-arterial extracorporeal membrane oxygenation (ECMO) salvage therapy was initiated in both cases as a bridge-to-recovery. Albumin dialysis was also commenced to further enhance elimination of amlodipine given its high plasma protein-binding properties. Both patients improved drastically once perfusion to vital organs was maintained by ECMO and eventually survived with good neurological outcomes and preserved cardiac contractility on discharge. This case report supports the growing evidence that although ECMO support represents a potentially life-saving salvage therapy for refractory poisoning-induced shock, escalation to ECMO must be considered and instituted early before irreversible multi-organ failure sets in to ensure good clinical outcomes.