To investigate the antipyretic effects and potential mechanism of Isodon eriocalyx ethanol extracts, the SD rats was injected by dry yeast subcutaneously to establish the model of fever. Experimental groups were divided into blank, model, positive drug paracetamol(150 mg/kg), low doses(200 mg/kg), high doses(800 mg/kg)of ethanol extracts of I. eriocalyx, rosmarinic acid(150 mg/kg), cirsimaritin(150 mg/kg)and maoecrystal D(150 mg/kg). After 4 hours of model establishment, the drugs were administered orally to each group; the blood and tissue samples were then collected 8 hours affer model establishment. Rectal temperature was detected to evaluate the antipyretic effects. The levels of tumor necrosis factor(TNF-α), arginine vasopressin(AVP), cyclic adenosine monophosphate(cAMP)and prostraglandin E2(PGE2)were measured to explore the potential mechanism. Results showed that the inoreased rectal temperature in rats was ameliorated by ethanol extracts of I. eriocalyx. Moreover, administration of ethanol extracts of I. eriocalyx could reduce the serum TNF-α levels and increase AVP levels in rats, decrease the levels of cAMP and PGE2 in hypothalamus and promote AVP secretion in ventral septal area of rats. However, there were no dramatic changes about rectal temperature and biochemical indicators mentioned above after administration of rosmarinic acid, cirsimaritin and maoecrystal D, respectively. In conclusion, ethanol extracts of I. eriocalyx exerted antipyretic effects on fever rats induced by yeast, which is probably due to the suppression of the secretion of TNF-α, cAMP and PGE2 and promotion of the excretion of AVP. However, the material basis of the antipyretic mechanism of this plant still remains to be further explored.