trans-Resveratrol, a natural polyphenol enriched in grape seed and skin, has been extensively investigated for its antioxidant, anti-inflammatory and anti-psychiatric properties. The present study examined the effects of trans-resveratrol on ameliorating anxiety-like behaviors and fear memory deficits induced by time-dependent sensitization (TDS) procedure, which is a classical animal model for mimicking posttraumatic stress disorder (PTSD). The results suggested that trans-resveratrol at doses of 10, 20 and 40 mg/kg (via gavage, i.g.) reversed TDS-induced decreases in the percentage of time spent in the center of arena, the open arm entries and time spent in the open arms in the open field and elevated plus maze tests. It also decreased the percentage of freezing time in the contextual fear paradigm that was increased in TDS treated rats. Further study suggested that TDS-induced abnormality in the limbic hypothalamus-pituitary-adrenal gland (L-HPA) axis was reversed by trans-resveratrol, i.e. it reversed increased adrenal gland index and corticotropin-releasing factor (CRF) levels, and rescued the differential expression of glucocorticoid receptor (GR) in the hypothalamus, hippocampus and amygdala. Neurobiological studies suggested that trans-resveratrol increased phosphorylation of cAMP response element binding protein (pCREB) and brain derived neurotrophic factor (BDNF) levels, which were decreased in rats subjected to TDS. These results provide compelling evidence that trans-resveratrol protects neurons against PTSD-like stress insults by regulation of L-HPA axis function and activation of downstream neuroprotective molecules, such as pCREB and BDNF expression.