Introduction <p>Ischemia–reperfusion injury (IRI) is a major concern in diabetic patients undergoing vascular procedures, causing significant damage to the liver and kidneys. The purpose of this study was to evaluate the protective effects of cerium oxide on the liver and kidneys of diabetic mice with lower extremity IRI.</p> Materials and Methods <p>Thirty Swiss albino mice were divided into five experimental groups: control (C), control diabetes (D), diabetes with cerium oxide (D-CEO₂), diabetes with IRI (D-IRI), and diabetes with IRI treated with cerium oxide (D-IRI-CEO₂). Diabetes was induced with streptozotocin (125&#xa0;mg/kg) and lower-extremity IRI was induced by clamping the infrarenal aorta. Cerium oxide was administered intraperitoneally to the 0.5&#xa0;mg/kg cerium oxide groups 30&#xa0;min before ischemia. Liver and kidney tissue samples were subsequently analyzed through biochemical assays measuring the total antioxidant status, total oxidant status, oxidative stress index, and paraoxonase-1, as well as histopathological examinations.</p> Results <p>The D-IRI group exhibited greater liver and kidney damage than the control group. The D-IRI-CeO₂ group displayed reduced liver and kidney damage compared to the D-IRI group. In both the D-IRI and D-IRI-CeO₂ groups, the total oxidant status, oxidative stress index, and paraoxonase-1 acitivity were higher, whereas the total antioxidant status levels were lower. In the D-IRI-CeO₂ group, there was a decrease in total oxidant status, oxidative stress index, and paraoxonase-1, whereas total antioxidant status increased compared to D-IRI.</p> Conclusion <p>Intraperitoneal cerium oxide reduces oxidative stress and mitigates liver and kidney damage in diabetic mice subjected to lower extremity ischemia–reperfusion injury.</p>