Objectives: Hwangryunhaedok-tang (HH) is a representative heat clearing multiherb prescription. We evaluated the protective effect of HH against heat stress exposure in mice. Methods: Six weeks old ICR mice were used for this study. After $43^{circ}C$ heat stress for 15 minutes, we evaluated the changes of motor activity and c-fos expression level to determine the proper heat stress and evaluation time. The subjects were divided into 4 groups (1. control group, 2. heat stress group with normal saline, 3. heat stress group with administration of 100 mg/kg, and 4. heat stress group with administration of 1000 mg/kg). After oral administration of HH once a day for 3 days, 2, 3, 4 groups were exposed to $43^{circ}C$ heat stress for 15 minutes. Then, we evaluated the motor activity for 120 minutes and analyzed the c-fos expression using western blot. We investigated the effect of HH and its ingredients on c-fos expressions after heat stress. The mice were administrated HH, Scutellariae Radix, Coptidis Rhizoma, Phellodendri Cortex, and Gardeniae Fructus for 3 days. After one hour of last treatment, the mice were exposed to heat stress at $43^{circ}C$ for 15 min. After two hours, the hypothalamus was dissociated and lysed to measure c-fos expression. Results: After oral administration of HH for 3 days, motor activity was recovered insignificantly. 100 mg/kg HH treatment reduced the c-fos expression after heat stress but insignificantly. Among the ingredients of HH, Coptidis Rhizoma and Scutellariae Radix treatment groups significantly reduced the c-fos after stress. Conclusions: These results show that Hwangryunhaedok-tang may be effective to reduce the heat stress response.