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Context: The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed. Objective: This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation. Materials and methods: Male Sprague-Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-a), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels. Results: Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-a by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p50.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p40.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters. Discussion and conclusion: MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis. ARTICLE HISTORY