Patchoulene epoxide (PAO), a tricyclic sesquiterpene isolated from the long-strored patchouli oil, has been demonstrated the anti-inflammatory activity in vivo based on our previous study. However, the gastroprotective effect of PAO still remains unknown. Therefore, in the present study, ethanol-induced gastric ulcer in rats was carried out to evaluate the anti-ulcerogenic activity of PAO and to elucidate the potential mechanisms that involved. According to our results, macroscopic examination revealed that pre-treatment with PAO signficantly reduced ethanol-induced gastric ulcer areas as compared with the vehicle group, which was also supported by histological evaluation. In addition, PAO was able to enhance the expressions of antioxidant enzymes including glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) as well as suppress lipid peroxidation indicated by down-regulation of malonaldehyde (MDA). Besides, the anti-inflammatory activity of PAO also contributed to gastroprotection characterized by reversing the imbalance between pro- and anti-inflammatory cytokines and modulating the expressions of NF-κB pathway-related proteins including p-IκBα, IκBα, p-p65 and p65. Furthermore, immunohistochemistry analysis exhibited potent anti-apoptosis effect of PAO as well, which appeared as down-regulation of caspase-3, Fas and Fasl protein expression. In conclusion, these findings suggested that PAO has gastroprotective activity against ethanol and this might be related to its positive influence on oxidative stress, inflammatory response and apoptosis cascade.