Doxorubicin (DOX) is a widely used chemotherapeutic agent however its clinical use is limited by cumulative cardiotoxicity. Epigallocatechin-3-gallate (EGCG), a main catechin in green tea, possesses a potent antioxidant, anti-apoptotic and anticancer properties. The current study aimed to investigate the potential protective effect of EGCG against DOX-induced cardiotoxicity. Firstly the potential cardioprotective dose of EGCG was screened at different doses (10, 20 and 40 mg/kg/day) against a single dose of DOX (15 mg/kg; i.p.). EGCG protected against DOX-induced ECG changes, leakage of cardiac enzymes (creatine kinase isoenzyme-MB, and lactate dehydrogenase) and histopathological changes. The dose of 40 mg/kg EGCG was selected for further assessment to address the EGCG cardioprotective mechanisms. EGCG was given orally 3 times/week for 4 consecutive weeks and DOX (2.5 mg/kg; i.p.) 3 times/week on the last 2 weeks. EGCG significantly ameliorated oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. DOX caused down-regulation of ErbB2 expression while EGCG pretreatment significantly increased ErbB2 expression indicating its effect on pro-survival pathway. Furthermore, DOX provoked apoptotic responses evidenced by increasing the expression of nuclear factor kappa-B, tumor suppressor protein p53, calpain 2, caspases 3 and 12. Additionally basal level of Hsp70 was reduced in DOX-intoxicated group. EGCG pretreatment significantly ameliorated these apoptotic signals indicating its anti-inflammatory and anti-apoptotic actions. In conclusion, EGCG possesses cardioprotective action against DOX-induced cardiotoxicity by suppressing oxidative stress, inflammation and apoptotic signals as well as activation of pro-survival pathways.