Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p<0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p<0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p<0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-alpha, and IL-1 beta mRNA, as well as protein expressions were significantly decreased (p<0.05) by fisetin treatment. It also significantly (p<0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-alpha, and IL-1 beta), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.