Drug intoxications remain a major challenge in pediatrics, particularly when involving uncommon medications such as tricyclic antidepressants, whose cardiotoxic and neurotoxic potential carries a high risk of mortality. We report the case of a 13-year-old girl with severe amitriptyline intoxication who was admitted to the Pediatric Intensive Care Unit with deep coma, ventricular arrhythmias and seizures. Despite initial treatment with bicarbonate, activated charcoal, vasoactive support and lipid emulsion therapy, hemodynamic and neurological instability persisted. Plasmapheresis was initiated as rescue therapy, leading to a progressive reduction in plasma amitriptyline levels and progressive clinical and neurological recovery, including normalization of the electroencephalogram and cardiovascular stabilization, which allowed extubation and withdrawal of hemodynamic support. This case highlights the potential role of plasmapheresis in severe tricyclic antidepressant intoxications when conventional measures are insufficient.