Diabetic cardiomyopathy (DCM) is a complication of diabetes results in high mortality due to its oxidative stress. The present study was designed to investigate the effect of rosemary extract and Hesperidin on hyperglycemia-induced oxidative stress, inflammation and cardiac injury in experimentally induced DCM in rats. Fifty rats were divided into five groups. Group Ι: rats fed on normal diet. Group Π: rats received a single dose of streptozotocin at a dose of (50 mg /kg body wt.). Group III: Rats treated with insulin 2 U/rat per day. Group IV: rats treated orally with Rosemary extract at a dose of (200 mg/kg body weight/day). Group V: rats treated with Hesperidin orally at a dose of (100 mg/kg body weight/day). Blood samples and cardiac tissue specimen were collected at the end of the experiment. The obtained results showed a marked increase in blood glucose concentration and upregulation in Endothelin-1(ET-1), Hypoxia inducing factor-1 α (HIF-1α), miR-29 and miRNA130b-3p gene expressions with hypermethylation in global DNA methyltransferase (DNMT) in cardiac tissue of DCM-induced group. Treatment with insulin, rosemary extract and hesperidin exhibited a significant decrease in blood glucose concentration and downregulation in Endothelin-1, miR-29 and miRNA130b-3p expressions with hypomethylation in DNMT, while, HIF-1α showed a significant upregulation as compared to DCM non treated group. In conclusion, these results indicated that rosemary extract and hesperidin may have great therapeutic potential in the treatment of DCM.