Abstract The present study was attempted to evaluate the therapeutic effects of activated protein C and/or hyperbaric oxygen in an animal model of heatstroke. Sixty-eight minutes heat stress (43 °C) initiated, the anesthetized rats were randomized to several groups and administered: 1) no resuscitation (vehicle solution plus normabaric air, 2) intravenous activated protein C (1 mg in 1 ml of normal saline per kg of body weight), 3) hyperbaric oxygen (100% oxygen at 202 kpa for 17 min), and 4) intravenous activated protein C plus hyperbaric oxygen. Another group of rats exposed to room temperature (26 °C) was used as normothermic controls. Blood sampling was 0 min, 70 min, and 85 min after heat stress initiated. When the vehicle-treated rats underwent heat exposure, their survival time values found were to be 19–25 min. Resuscitation with activated protein C or hyperbaric oxygen significantly and equally improved survival during heatstroke (134–159 min). As compared with those of activated protein C or hyperbaric oxygen alone, combined activated protein C and hyperbaric oxygen significantly had higher survival time values (277–347 min). All vehicle-treated heatstroke animals displayed systemic response, hypercoagulable state, and hepatic and renal dysfunction. Combined activated protein C and hyperbaric oxygen therapy reduced these heatstroke reactions better than activated protein C or hyperbaric oxygen alone. The results indicate consequently, combined activated protein C and hyperbaric oxygen therapy heightens benefit in combating heatstroke reactions.