Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by the cardiotoxicity. Ghrelin, a multi-functional peptide hormone with metabolic regulation in energy homeostasis, plays important roles in cardiovascular protection. Now, the underlying mechanisms of ghrelin against DOX-induced cardiomyocyte apoptosis and atrophy are still not clear. In the present study, we revealed an autophagy-dependent mechanism involved in ghrelin's protection against DOX-induced cardiomyocyte death and size decrease. We observed that DOX insult induced remarkable mortality and cardiac dysfunction in mice, and increase in LDH leakage, cardiomyocyte apoptosis and decrease in cell viability and size in mouse hearts and H9c2 cell cultures, which were effectively improved by ghrelin supplement. We further observed that the strong autophagy stirred by DOX exposure was paralleling with the serious apoptosis and size decrease in cardiomyocytes. Ghrelin, like an autophagy inhibitor, 3-MA, inhibited the DOX-induced autophagy and attenuated cardiomyocyte apoptosis and size decrease. Furthermore, ghrelin significantly reduced the intercellular oxidative stress level, a strong autophagy trigger, partly by augmenting the expression and activities of the endogenous anti-oxidative enzymes. After the further investigation in the post signaling pathways of ghrelin receptors in H9c2 cells, including ERK, p38/MAPK, JNK, AMPK and Akt, we observed that ghrelin supplement only reduced the DOX-activated AMPK and augmented the DOX-down regulated p38-MAPK and mTOR phosphorylation. Our results indicated that ghrelin effectively improved the cardiomyocyte survival and size maintenance by suppressing the excessive autophagy through both ROS inhibition and mTOR induction through suppressing AMPK activity and stimulating p38-MAPK activity.