Vasoplegic syndrome is a type of distributive shock characterized by mean arterial pressure of less than 65 mmHg, with normal to high cardiac output and often refractory to fluid resuscitation, high doses of intravenous vasopressors, and inotropes. It is usually observed after cardiac and solid organ transplantation surgeries.Here, we report a 56-year-old female patient who presented with a profound vasoplegia manifesting as lethargy and confusion in the setting of amlodipine toxicity. This case of severe vasoplegia was refractory to all conditional lines of medical management reported in the literature. The mainstay treatment modalities for vasoplegia include volume resuscitation, catecholamines, vasopressin, angiotensin II, and possibly methylene blue in unresponsive cases. Our patient was given hydroxocobalamin in favor of methylene blue, given the history of serotonin reuptake inhibitors use, which would have caused a life-threatening serotonin syndrome. Hydroxycobolamine resulted in a dramatic clinical recovery, suggesting its potentially significant role in refractory vasoplegia.