Transient global amnesia is a clinically distinct syndrome characterized by the acute inability to form new memories. It can last up to 24 hours. The diagnosis is dependent on eliminating other more serious etiologies including toxic ingestions, acute strokes, complex partial seizures, and central nervous system infections. Transient global amnesia confers no known long-term risks; however, when abnormal signs or symptoms are present, they take precedence and guide the formulation of a differential diagnosis and investigation. In witnessed transient global amnesia with classic features, a minimalist approach is reasonable, avoiding overtesting, inappropriate medication, and medical interventions in favor of observation, ensuring patient safety, and reassuring patients and their families. This review provides a detailed framework for distinguishing transient global amnesia from its dangerous mimics and managing its course in the emergency department.