Metabolic syndrome (MetS) and ischemic heart disease (IHD) are interrelated conditions contributing to significant cardiovascular morbidity and mortality worldwide. Emerging evidence highlights the role of genetic polymorphisms in modulating susceptibility to these disorders. This review focuses on the impact of Renalase and Sirt1 gene polymorphisms in patients diagnosed with MetS and IHD. Renalase, a secreted flavoprotein, plays a pivotal role in blood pressure regulation, glucose metabolism, and cardiovascular protection, while Sirt1, a NAD+-dependent deacetylase, regulates energy metabolism, inflammation, and oxidative stress. Polymorphic variations in these genes may influence their expression and functionality, exacerbating metabolic and cardiovascular derangements observed in MetS with concurrent IHD. This review synthesizes current findings regarding the genetic variants of Renalase and Sirt1 and their association with metabolic dysregulation, endothelial dysfunction, and atherosclerosis progression. Additionally, it explores the potential for these polymorphisms to serve as predictive biomarkers and therapeutic targets. Understanding the genetic interplay of Renalase and Sirt1 polymorphisms could provide insight into personalized medicine approaches, enhancing risk stratification and management of MetS patients predisposed to IHD.