Heat stroke (HS) is a life-threatening illness characterized by core body temperatures above 40 °C coupled with central nervous system (CNS) dysfunction, including delirium, convulsions, and/or coma. Its morbidity has increased dramatically in the past few decades. Multiple organ dysfunction syndrome (MODS) is not only the most serious complication of HS, but also the leading cause of deaths. Understanding the pathogenesis, characteristic and advancement pattern of MODS caused by HS will have a profound effect on the clinical treatment, research and mortality decrease. The pathogenesis, injury characteristic of each system and organ, and treatment methods were summarized in this review so as to deepen the clinical recognition of this disease.