A multi-micronutrient compound is composed of ascorbic acid, thiamin, riboflavin, vitamin B6, niacin, folic acid, K, Na, Ca, Mg, Cu, Mn, Fe and Zn. In order to explore the effect of the multi-micronutrient on heat adaptation and its probable mechanism, heat-exposed Drosophila melanogaster, mice and rats were observed. The results showed that the multi-micronutrient could significantly increase the survival rate of heat-exposed Drosophila melanogaster and prolong the survival time and swimming time of mice under high temperature. The results indicated that the significant influence of multi-micronutrients on heat adaptation could be the result of enhancing the glucocorticoid receptor activity in hepatic cytosol in the heat-exposed rats, inhibiting liver phospholipase A2 activity in the heat-exposed rats, increasing serum SOD activity and decreasing serum MAD content in the heat-exposed rats, as well as increasing level of HSP70 in the heat-exposed Drosophila melanogaster. The results suggested that the effect of enhancing heat adaptation might be related to improving neuroendocrine regulation, enhancing anti-oxidative function against the damage of free radicals as well as increasing HSP70 content.