Sepsis/multiple organ dysfunction syndrome is the leading cause of death in critically ill patients. Recently, it has been suggested that hydrogen gas (H2) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical (•OH, the most cytotoxic reactive oxygen species). We have found that H2 inhalation significantly improved the survival rate and organ damage of septic mice with moderate or severe cecal ligation and puncture. In the present study, we investigated the effects of 2% H2 treatment on survival rate and organ damage in zymosan (ZY)-induced generalized inflammation model. Here, we found that 2% H2 inhalation for 60 min starting at 1 and 6 h after ZY injection, respectively, significantly improved the 14-day survival rate of ZY-challenged mice from 10% to 70%. Furthermore, ZY-challenged mice showed significant multiple organ damage characterized by the increase in serum biochemical parameters (aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine), as well as lung, liver, and kidney histopathological scores at 24 h after ZY injection, which was significantly attenuated by 2% H2 treatment. In addition, we found that the beneficial effects of H2 treatment on ZY-induced organ damage were associated with the decreased levels of oxidative product, increased activities of antioxidant enzyme, and reduced levels of early and late proinflammatory cytokines in serum and tissues. In conclusion, this study provides evidence that H2 treatment protects against multiple organ damages in ZY-induced generalized inflammation model, suggesting the potential use of H2 as a therapeutic agent in the therapy of conditions associated with inflammation-related multiple organ dysfunction syndrome.