Abstract Body: A growing body of evidence indicates that the prevalence of cardiovascular diseases is high in diabetic individuals and is the primary cause of death in them. Although significant progress has been made in understanding the cardiometabolic disorders, a gap remains in elucidating the mechanistic cause of cardiovascular disease associated with diabetes; thus, very few effective therapeutic strategies are available. In this study, we highlight a pivotal role of one of the paralogs of the chloride intracellular channel (CLIC) family, CLIC1, in cardiac complications associated with diabetes. Type-2 diabetes was induced in wild-type and CLIC1-knockout mice by high-fat diet consumption and administering a low dosage of streptozotocin. Echocardiography analysis indicated that both male and female diabetic CLIC1-knockout mice showed early onset of diastolic dysfunction and systolic dysfunction in comparison to diabetic wild-type mice. Cardiac fibrosis and troponin levels were augmented in diabetic CLIC1-knockout mice in comparison to wild-type mice. We also observed siRNA-mediated knockdown of Clic1 expression in cardiomyocytes exacerbated cell death via apoptosis when cultured in palmitic acid. Thus, highlighting a cardioprotective role of CLIC1 in high glucose stress. Additionally, we observed increased mitochondrial reactive oxygen species generation and endoplasmic reticulum stress marker proteins in CLIC1-knockout diabetic myocardium compared to that of wild-type. These results establish a vital role of CLIC1 in the onset of diabetes associated cardiomyopathy, probably by inducing endoplasmic stress for the first time. Thus, highlighting the importance of a CLIC1-specific therapeutic strategy against diabetes-related cardiomyopathy.