Background: Despite advancements in critical care, hemorrhage remains a leading cause of potentially survivable deaths in civilian and military settings. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a viable technology that could be used in the pre-hospital setting. However, the potential complications of prolonged REBOA use, especially in the military setting where the prehospital phase could exceed 2 hours, are not completely understood with regards to organ damage susceptibility to prolonged REBOA use. Materials and methods: Fifteen male Yorkshire swine underwent a 40% volume-controlled hemorrhage over 20 minutes. Animals were then randomly assigned (n = 5/group) to REBOA inflation times of 120, 180, and 240 minutes, followed by 1 hour of resuscitation with shed whole blood and crystalloid before euthanasia. Samples were collected for blood gas analysis, chemistry, Luminex, enzyme-linked immunosorbent assays (ELISAs), and histology. Results: Metabolic acidosis increased with prolonged REBOA inflation times along with inflammation as shown by increases in interleukin (IL)-6 and neutrophil levels. Organs most susceptible to prolonged REBOA inflation times were the liver and intestines as demonstrated by histology. Conclusion: While REBOA has been shown to effectively staunch hemorrhage and improves survival, complications exist for prolonged REBOA inflation times. The results of this study demonstrate that the liver and intestines are particularly susceptible to prolonged REBOA inflation out to 4 hours, in addition to increased metabolic acidosis and systemic inflammation. These findings should help guide clinicians while using REBOA over a prolonged period of time to improve survival and mitigate potential REBOA-associated ischemic organ damage.