Optimal selections of innate behaviors that enable animals to adapt to particular conditions, whether environmental or internal, remain poorly understood. We report that mice under acute (8 h) sleep deprivation had an enhanced innate escape response and upregulation of c-fos expression in multiple brain areas that regulate wakefulness. By comparison, adrenalectomized mice under the same sleep deprivation condition displayed an even more exaggerated escape response and these wake-regulating brain areas were even more active. This suggests that acute sleep deprivation enhances innate escape response, possibly by altering wake state without causing significant anxiety. We also report that the hypothalamic-pituitary-adrenal axis feedback under sleep deprivation prevents an exaggerated escape response by modulating wake-regulating brain areas. Taken together, our findings suggest that animals prioritize escape response over sleep, as the need of both behaviors simultaneously increase. We also provide an insight into the neural mechanisms underlying the interaction between sleep and innate escape response. (C) 2020 Published by Elsevier Inc.