Cardiac injury is a major complication of the oxidative stress-generating anticancer drug doxorubicin (DOX). The green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been reported to play a cardioprotective role in diseases associated with oxidative stress. The objective of this study was to investigate whether EGCG can protect against DOX-induced toxicity in cardiomyocytes. The data showed that EGCG protected the cardiomyocytes from DOX-mediated cardiotoxicity, as evidenced by decreased lactate dehydrogenase (LDH) activity and increased cell viability in a dose-dependent manner. EGCG treatment also decreased malondialdehyde content and increased protein expression and activities of manganese superoxide dismutase (MnSOD), catalase, and glutathione peroxidase. Furthermore, treatment with EGCG decreased reactive oxygen species (ROS) production and apoptosis. This study suggests that EGCG could protect cardiomyocytes from DOX-induced oxidative stress by attenuating ROS production, apoptosis, and increasing activities and protein expression of endogenous antioxidant enzymes.