The aim of this study was to investigate the possible protective role of Hydrogen sulfide on chronic unpredictable stress (CUS) -induced gastric lesions. Materials and methods: 40 rats were divided into 4 groups: control group, stressed rats group, stressed + Aminooxyacetic acid (AOAA) (inhibitor of H2S synthesis; 50mg/kg/48hour; IP), stressed + Sodium hydrosulfide (NaHS) (donor of H2S, 5mg/kg/48hour; IP). In all the groups exposed to CUS, a set of chronic unpredictable stressors was applied for 6 weeks in random order. At the end of experimental protocol blood samples, gastric content and gastric tissues samples were collected. Gastric tissues histopathological changes were evaluated by macroscopic and microscopic examination. Gastric content pH, serum MDA level, whole blood GSH level were estimated. Expression of Caspase-3 (apoptotic marker) and BCL-xl (anti-apoptotic marker) was assessed by immunohistochemistry. Results: In all the groups exposed to CUS, there was a significant reduction in gastric pH value and a range of gastric lesions ranging from superficial to deep ulceration as evident by macroscopic and microscopic examination. Also, there was significant elevation in MDA serum level and significant reduction in anti-oxidant GSH blood level. In all stressed rats, the expression of Caspase-3 was significantly higher whereas a significant decrease in expression of anti-apoptotic protein BCL-xl was observed. These findings were aggravated by AOAA while using NaHS improved them. Conclusion: it seems that increasing bioavailability of H2S could have a protective role against CUS induced gastric lesions. The results suggest that this protection could be through anti-oxidant and anti-apoptotic effects.