Stress disrupts a variety of neural processes, including reducing levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. In contrast, exercise increases BDNF and is beneficial for health and cognition. Irisin is a myokine that is released into circulation during exercise. Although its main known functions are browning white adipose tissue and improving glucose homeostasis, Irisin also mediates the activation of an exercise-induced BDNF-mediated neuroprotective pathway in the hippocampus. Therefore, we tested the hypothesis that Irisin can counteract the deleterious effects of acute stress when directly injected into the hippocampus. To test our hypothesis, we used a 3-hr long physical restraint stress event in adult female and male mice. Acute stress resulted in sex-dependent increased anxiety-like behaviors and memory impairment in a combined open field/novel object recognition (OF/NOR) test, affecting male mice only. Moreover, acute stress also reduced skin temperature and body weight in both females and males. We then injected Irisin into the hippocampus via bilateral stereotaxic injection and repeated the acute stress paradigm and combined OF/NOR test. We found that Irisin partially blocked stress-induced anxiety-like behavior and memory impairment in male mice, while also preventing the reduction in skin temperature and body weight. In females Irisin only prevented the body weight reduction but showed no beneficial effects on neurobehaviors. Our results suggest a novel role for Irisin in counteracting acute stress-induced neurobehavioral and physiological abnormalities. Also, our results support the idea that exercise can be a potentially effective tool to promote the maintenance of healthy neural function. (PsycInfo Database Record (c) 2020 APA, all rights reserved).