Abstract: Background and Objective: Doxorubicin (DOX) is conventional chemotherapy for several types of malignancies although it induces considerable oxidative damage in different physiological systems. The present study aimed to examine whether the co-administration of naringenin (NG) and losartan (LOS) can produce additional protective effects against DOX-induced cardiac, hepatic and renal toxicities in rats. Materials and Methods: The LT and/or NG 2 week’s pre-treated animals were challenged with intraperitoneal DOX (15 mg kg–1). One week later, cardiac, hepatic and renal tissues along with serum were collected for biochemical and histopathological evaluations. Results: The altered histological architecture of the cardiac, hepatic and renal by DOX were restored by LT and NG treatments. Combining both compounds showed augmented protective effects. The LT and NG combination significantly ameliorated DOX associated elevation in serum inflammatory cytokines. In addition, DOX challenge induced cardiac, hepatic and renal toxicities along with disturbances in the biological oxidative defense capabilities manifested by elevated lipid peroxidation products, lowered glutathione levels and inhibited antioxidant enzymes activities. Co-administration of LT and NG markedly improved oxidative stress biomarkers and shifted the serum aminotransferases, creatinine, urea, lactate dehydrogenase and creatine kinases to their normal levels. Conclusion: Merging LT and NG therapies revealed significant advantages over single therapy with regards to their antioxidant and anti-inflammatory actions, which suggested a synergistic value of their combination.