Globally, diabetes mellitus (DM) is one of the most occurred metabolic diseases, involving an increased level of blood glucose in the body. In general, DM patients grow many comorbidities including coronary heart disease, overweight gain, and stroke. Myocardial ischemia (MI) is a type of coronary heart disease, it occurs when heart muscles lost the ability to pump blood accurately. Though DM and MI are not associated but many biological functions of both disease match with each other. Our objectives were to uncover the association between the DM and MI using a bioinformatics approach with bio-molecular signature. We compare both datasets with the Venn diagram, the outcomes showed that 144 genes were overlapped in both disease. The GO analysis revealed that the majority amount of genes were connected with the cytokine-mediated signaling pathway, cytokine activity, and membrane raft. Pathway analysis explored the common 144 genes that were enriched with the AGE-RAGE signaling pathway in diabetic complications, malaria, and pathways in cancer. A protein-protein interaction (PPI) network was constructed using the Cytoscape. From where we identified 10 significant genes (INS, ALB, IL6, TNF, VEGFA, IL10, CCL2, IL1B, CXCL8, and ICAM1) according to their connectivity range using cytoHubba tool. Drug target analysis reveals that the dexamethasone CTD 00005779 target is the most associated with all the hub genes. Our analysis showed the genetic and biological functional associations between DM and MI. The outcomes of the study will help in future medications development of DM and MI.