Doxorubicin (DOX) is an effective anticancer drug, however its clinical application is limited due to its cardiotoxicity. Therefore, understanding the mechanisms of cardiotoxicity induced by DOX is essential. We found that the level of miR-378 was decreased in the hearts of DOX-treated rats. Increasingthe expression of miR-378 resulted in a decrease of lactate dehydrogenase (LDH) upon DOX treatment in vitro by targeting lactate dehydrogenase A (LDHA). Furthermore, bioinformatics analysis indicated that cyclophilin A (PPIA), a regulator of apoptosis, is also a direct target gene of miR-378. We confirmed this by Western blot. Our results also showed that the overexpression of miR-378 inhibited the hyperactivation of ER stress signaling induced by DOX. In addition, MiR-378 overexpression was found to protect cardiomyocytes from DOX-induced energy imbalance and apoptosis of mitochondria. These results may allow for a therapeutic approach that overcomes the cardiotoxicity of DOX-based treatments for cancer.