Anandamide is a cannabinoid receptors agonist that showed a protective effect against intestinal I/R model. However, its modulatory effect on I/R-induced gastric ulcer has not been previously elucidated. Therefore, the aim of this study was to delineate this modulatory effect of anandamide on gastric ulcer and the possible involvement of the liver. Rats were randomized into sham, I/R and anandamide treated group (1.5μmol/kg). Gastric I/R caused an increase in the gastric ulcer index in addition to elevation of the inflammatory mediators TNF-α, nuclear factor kappa-B (NF-κB), and MPO along with a significant decrease in adenosine monophosphate protein kinase (AMPK) activity; this effect was shown both in the stomach and liver. Moreover, the gastric insult resulted in an imbalance in the redox system, where it elevated the lipid peroxidation content along with a noticeable decrease in the defense system (GSH, CAT and SOD). Additionally, I/R caused a marked increase in the serum activity of the aminotransferases ALT and AST, documenting the involvement of liver injury with gastric I/R model. Pre-administration of anandamide proved its anti-inflammatory effect by decreasing the measured inflammatory parameters and increased that of AMPK. Regarding its endowed antioxidant property, anandamide enhanced tissue activity/content of CAT, SOD, as well as GSH, besides normalizing the MDA level. Conclusion: the protective mechanisms of anandamide against I/R-induced gastric ulcer and liver injury may be mediated by modulation of oxidative stress through the improvement of the endogenous defense system. In addition, the anti-inflammatory effect of anandamide may be facilitated via the AMPK and NF-κB pathways.