We evaluated the ameliorative role of umbelliferone in kidney, heart, and lung damage induced by renal ischemia/reperfusion (I/R) injury in rats. Umbelliferone was given orally to rats 60 min before ischemia. Ischemia was induced for 50 min and then reperfusion for 3 hr. The antioxidant enzymes, myeloperoxidase (MPO) activity, malondialdehyde (MDA) content, and cytokine levels in the kidney, heart, and lung were measured by ELISA. Moreover, histopathological changes were monitored. Renal I/R-induced oxidative stress in the organs by decreasing antioxidant enzymes. However, umbelliferone pretreatment enhanced superoxide dismutase (SOD) and glutathione (GSH), levels, reduced MDA and MPO levels. Renal I/R increased in tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) levels, and histopathological changes but these effects were inhibited with umbelliferone pretreatment. Furthermore, umbelliferone increased in nitric oxide synthase (eNOS) level under ischemia conditions. Our results indicated that pretreatment of umbelliferone-ameliorated damages in remote organ induced by renal I/R through suppressing oxidative stress and modulating inflammatory responses.