Approximately 30% of poison exposures reported to centers each year are either referred to or initiated within a health care facility. Among these exposures, undifferentiated poisoned patients are among the most challenging cases faced in the emergency department. Airway, breathing, circulation (ABCs) is central to the management of unknown poisoned patient. After initial stabilization, taking a systematic approach presented here may be beneficial to the clinician. This includes considering key additional history, a possible toxidrome, and data in the form of vital signs, physical examination, laboratory analysis, ECG, and imaging. After which a tailored approach to supportive care, decontamination, possible antidotes, and enhanced elimination techniques will improve outcomes.