Background: Recently, the resuscitative endovascular balloon occlusion of the aorta (REBOA) has become widespread in hemorrhagic shock (HS). It temporarily increases the proximal blood pressure (pBP); but sacrifices the distal blood flow to the visceral organs, causing ischemic injury. We previously reported that hydrogen (H 2 ) gas inhalation mitigated ischemic injury and improved survival in rats with HS; however, during REBOA use, the H 2 gas was not delivered to the ischemic organs as it is distributed via the bloodstream. Therefore, we hypothesized that intra-aortic irrigation of H 2 -containing solution into the downstream of REBOA would mitigate ischemic injury. Methods: Herein, a swine liver injury with volume-regulated HS model was used. The female swine (around 40 kg, n = 16) were divided into two groups; a H 2 -containing solution irrigation (H 2 group) and saline irrigation (C group). After HS induction (20% of estimated total blood volume), the liver injury was initiated (20% of total liver volume). The REBOA was inflated during predefined time (60 min and 90 min) and intra-aortic irrigation to downstream of REBOA was started. The hemodynamic parameters, blood samples, and pathological changes were evaluated. Results: The elevation in lactate, interleukin 6, and syndecan levels were significantly suppressed over time in the H 2 group than in C group (p < 0.05). The pBP tended to decrease during REBOA in the C group; however, it remained higher in H 2 group (p < 0.05). Pathologically, the ischemic changes, such as liver sinusoidal enlargement and intestinal villi flattening and inflammatory infiltration were identified in the C group but not in H 2 group. Conclusion: The REBOA with downstream intra-aortic irrigation using H 2 -containing solution for liver injury with HS stabilizes hemodynamics, suppresses cellular injury, and mitigates organ damages. These results in large animals can be immediately applied to clinical use in humans.