The significance of grapes and grape-derived products as healthy foods is well established. Beyond their delightful taste and flavors, grapes offer numerous medicinal benefits due to a wide spectrum of bioactive compounds. These phytochemicals have been extensively studied for their potential to prevent metabolic syndrome. This chapter discusses the effects of grape polyphenolics in preventing or mitigating metabolic syndrome, highlighting several targets and reviewing their mechanistic effects. Adopting a diet that includes grapes may help address the metabolic clusters associated with this condition. Understanding the interplay between bioactive metabolites, gene expression, and phenotype is crucial for elucidating the complex mechanisms underlying grape-mediated protection against metabolic syndrome. Studies in rodents have shown that consuming grape products impacts multiple factors, including metabolic activity and subsequent metabolic adaptation, in models of metabolic syndrome. Additionally, evidence from clinical studies supports the significant role of grapes in combating metabolic syndrome. This chapter will explore the therapeutic potential of grape polyphenolics in managing metabolic syndrome, potential mechanisms of action, future challenges, and research directions related to the effects of grapes on this condition.