<p>Emerging evidence indicates that dietary polyphenolic compounds can mediate stress-induced psychological impairment. Particularly, resveratrol shows promise in alleviating depression-like symptoms in animal models due to its ability to reduce inflammation and oxidative stress and promote neuroplasticity. Resveratrol and other polyphenols may modulate pathways such as Sirtuin 1 (SIRT1) and Nuclear Factor- kappa B, which are involved in inflammatory and apoptotic processes in the brain. By activating SIRT1, a deacetylase, resveratrol influences proteins in stress resistance and inflammation. Resveratrol and other polyphenols hold potential as natural therapeutic agents by influencing DNA methylation, histone modifications, and non-coding RNA expression. In addition to their epigenetic modulation, polyphenols possess potent antioxidants and anti-inflammatory properties. They can reduce oxidative stress by scavenging free radicals and activating nuclear factor-erythroid 2 related factor 2, which upregulates antioxidant enzymes. They also suppress neuroinflammation by inhibiting the production of pro-inflammatory cytokines. This multi-faceted action, particularly their influence on epigenetic mechanisms and inflammatory pathways, supports the hypothesis that polyphenols and resveratrol can mediate stress-induced depression. This review discusses the antidepressant capabilities of grape-derived polyphenols in the context of SIRT1-mediated epigenetic modifications implicated in the onset of major depressive disorder.</p>