Purpose: Acute peritonitis has remained a fatal disease despite of recent advances in care and treatment, including antibiotic and anticoagulant treatments. The cause of death is mostly sepsis-induced multiple organ failure. Oxidative stress can play an important role in this situation, but antioxidant therapy to capture any excessive reactive oxygen species has not yet been fully established. Methods: Two experiments were performed. In the first experiment, we confirmed the effects of peritoneal lavage with hydrogen-rich saline (HRS) after a cecal ligation and puncture (CLP) operation in rats. In the second experiment, the changes in the hemodynamic state following this procedure were observed in a porcine model of abdominal sepsis to evaluate its safety and utility. Results: Peritoneal lavage with HRS significantly improved the survival after CLP in rats, and it ameliorated the levels of sepsis-induced organ failure. Moreover, it showed anti-inflammatory and anti-apoptosis as well as antioxidant effects. The second experiment demonstrated the potential safety and feasibility of this procedure in a large animal model. Conclusion: This procedure can improve survival after sepsis through mitigating the sepsis-induced organ failure by inhibiting oxidative stress, apoptosis, and inflammatory pathways. Peritoneal lavage with HRS may therefore be an effective, safe, and practical therapy for patients with acute peritonitis.