Hyperactive delirium with severe agitation is a clinical syndrome of altered mental status, psychomotor agitation, and a hyperadrenergic state. The underlying pathophysiology is variable and often results from sympathomimetic abuse, psychiatric disease, sedative-hypnotic withdrawal, and metabolic derangement. Patients can go from a combative state to periarrest with little warning. Safety of the patient and of the medical providers is paramount and the emergency department should be prepared to manage these patients with adequate staffing, restraints, and pharmacologic sedatives. Treatment with benzodiazepines, antipsychotics, or ketamine is recommended, followed by airway protection, supportive measures, and cooling of hyperthermia.