Stress ulceration frequently occurs as a result of major stressful events and hydroxyl radical (⋅OH) is one of the major causative factors for it. Recently, it has been proved that hydrogen, a potent selectively ⋅OH scavenger, can effectively protect animals against ROS-induced tissue damage. In like manner, we hypothesize that hydrogen may have a protective effect against stress ulceration. Gastric ulceration was induced by the method of cold restraint stress. Rats in the hydrogen treatment group received hydrogen-rich saline (10 mL/kg body weight) 5 min before the stress. At 6h post-stress, gastric corpus mucosa was harvested for the measurement of malondialdehyde, protein carbonyl, 8-hydroxy-desoxyguanosine, glutathione, superoxide dismutase, myeloperoxidase, TNF-α, IL-1β and cytokine-induced neutrophils chemoattractant-1. In addition, western blotting was used to determine the expression of p38 MAPK, P-p38 MAPK, P-JNk, JNK, Bcl-xl, Bax and cleaved caspase-3. Nuclear translocation of NF-κB was assessed by electrophoretic mobility shift assay. Gastric mucosa structure and mucosal epithelial cells apoptosis were measured at 12h post-stress. Our present study showed that hydrogen treatment lessened the stress-induced lipid peroxidation, protein carbonyl and DNA oxidant and improved tissue antioxidant potential. In addition, hydrogen mitigated inflammatory response and neutrophils infiltration with suppressing the activity of P-p38 MAPK, P-JNk and NF-κB. Importantly, hydrogen ameliorated gastric mucosa damage with preventing cell apoptosis. Furthermore, the up-regulation of cleaved caspase-3, Bax and down-regulation of Bcl-xl expression were blocked by hydrogen treatment. In conclusion, hydrogen treatment effectively ameliorated stress-associated gastric mucosa damage via its anti-oxidant, anti-inflammatory and anti-apoptotic effects.