Cancer and cardiovascular disease are the two leading causes of mortality in Canada. Unfortunately, these two diseases are intricately linked, as the anti-cancer drug, doxorubicin (Dox) can cause detrimental effects on the heart. Amongst the various potential mechanisms of Dox-induced cardiomyopathy (DIC), little is known about the role of endoplasmic reticulum (ER) stress which may lead to cardiomyocyte apoptosis and heart failure. We used rat cardiomyocytes as well as an in vivo murine model to characterize Dox-induced ER stress and subsequent changes in cardiac structure and function. To date, there are no approved pharmacological therapies for the prevention and/or treatment of DIC. We investigated the therapeutic potential of two compounds: 1) An anti-inflammatory cytokine, Interleukin-10 (IL-10); and 2) an anti-diabetic medication, Empagliflozin (EMPA), in the setting of DIC. In isolated cardiomyocyte studies, Dox (10 µM) induced ER stress and apoptosis. We identified cleaved activating transcription factor 6α (ATF6α) as the major ER transmembrane protein which is upregulated following Dox treatment. Dox-induced ER stress changes were mitigated by the pretreatment of both IL-10 (10 ng/ml) and EMPA (500 nM). IL-10 primarily worked through downregulating ATF6 cleavage and promoted cell survival by downregulating caspase-12 activation and phosphorylation of c-Jun N-terminal kinase. On the other hand, EMPA mitigated ER stress via activation of inositol-requiring kinase 1α (IRE1α) and downregulation cleavage of ATF6α. The effects of EMPA in decreasing oxidative stress, inflammation, and apoptosis were also noted. In the rat model of DIC (cumulative dose, 15 mg/kg), there was downregulation of ER chaperones followed by an increase in apoptosis. Prophylactic and concurrent treatment of EMPA (10 mg/kg body weight, daily) mitigated ER stress via upregulation of ER chaperones and downregulation of ER stress induced apoptosis. There were significant detrimental changes in the structure and function of the myocardium by the end of the experiment in the Dox group which were rescued by EMPA treatment. These preclinical studies suggest that ER stress plays an intermediary role in worsening DIC which can be modulated by IL-10 and/or EMPA. The molecular details in this study provide a rationale for the prophylactic use of EMPA to reduce DIC.