Post-traumatic stress disorder (PTSD) has become a major psychiatric and neurological issue. Resveratrol is shown to be effective on depression and anxiety. However, the mechanism of anti-PTSD-like effects of resveratrol remains unknown. The present study aimed to explore the possible molecular and cellular mechanisms underlying the anti-PTSD-like effects of resveratrol. Following a 2-day exposure to inescapable electric foot shocks, animals were administered resveratrol (10, 20, and 40 mg/kg, i.g.) during the behavioral tests, which included contextual freezing measurement, elevated plus maze test, staircase test, and open field test. Similar to the positive control drug sertraline (15 mg/kg, i.g.), the behavioral deficits of stressed mice were blocked by resveratrol (20 and 40 mg/kg, i.g.), which reversed the increased freezing time in contextual freezing measurement and the number of rears in the staircase test and blocked the decrease in time and number of entries in open anus in the elevated plus maze test without affecting the locomotor activity in the open field test. In addition, resveratrol (20 and 40 mg/kg, i.g.) antagonized the decrease in the levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus. Furthermore, long-term resveratrol attenuated the dysfunctions of hypothalamic-pituitary-adrenal axis simultaneously. Collectively, the evidence indicated that the anti-PTSD-like effects of resveratrol were associated with the normalization of biosynthesis of neurosteroids in the brain and prevention of the hypothalamic-pituitary-adrenal axis dysfunction.