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This study evaluated the cardioprotective properties of Boesenbergia rotunda extract (BrE) against doxorubicin (DOX) induced cardiotoxicity. Rats received oral gavage of BrE for 28 days and DOX (5 mg/kg/week for 3 weeks). Thereafter the animals were sacrificed, blood and cardiac samples were collected for biochemical, histological and immunohistochemical analyses. The results indicated that BrE attenuated DOX triggered body and cardiac weight loss and prevented against cardiac injury by mitigating histopathological alterations in cardiac tissues as well as serum cardiac function enzymes. BrE significantly reduced serum levels of aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), troponin T (TnT) and creatine kinase-MB (CK-MB) in DOX-treated rats. Furthermore, BrE alleviated cardiotoxicity by reducing DOX instigated oxidative stress and potentiating the level of glutathione, as well as the activities superoxide dismutase and catalase in cardiac tissues. In addition, BrE significantly decreased the characteristic indices of DOX-induced cardiac inflammation and apoptosis. Immuno-histochemical analysis revealed that BrE decreased the stain intensity of p53 and myeloperoxidase (MPO) proteins compared to the DXB alone group. In conclusion, our results indicated that BrE modulated oxidative stress, inflammation and apoptosis to attenuate DOX-induced cardiac damage.