This study investigated the protective effect of ellagic acid (EA) against diabetic cardiomyopathy (DC) in streptozotocin (STZ)-treated rats and examined if the mechanism of protection involves modulating silent information regulator 1 (SIRT1). Adult male rats were divided into 5 groups (n = 12/each) as control, control + EA, diabetes mellitus (DM), STZ + EA, and STZ + EA + EX-527 (a SIRT1 inhibitor). With a hypoglycemic and insulin-releasing effect, EA preserved cardiomyocyte structure and suppressed the increase in heart weights and collagen deposition in the left ventricle (LV) of DM rats. Concomitantly, EA improved LV systolic and diastolic functions; reduced serum levels of creatinine kinase-MB (CK-MB), brain natriuretic peptide (BNP), and troponin-I, downregulated transforming growth factor beta 1 (TGF-β1), smad3, and cleaved caspase-3, and increased Bax/Bcl-2 ratio. Of note, EA increased the expression and activity of SIRT1 and suppressed the acetylation of nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NF-κB), smad2, and forkhead box, class O (FOXO1) in the LVs of both the control and diabetic groups. These effects were associated with a significant reduction in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor kappa (TNF-κ), and interleukin 6 (IL-6) levels and activity of NF-κB but with increased activity Nrf2 and levels of glutathione (GSH), superoxide dismutase (SOD), and Bcl-2. All these effects were abolished by EX-527. In conclusion, EA protected against DC by its hypoglycemic, antioxidant, anti-inflammatory, and anti-fibrotic, and anti-apoptotic effects through upregulation and activation of SIRT1.