Resveratrol, a natural polyphenol with antioxidative and anti-inflammatory properties, has garnered attention for its potential therapeutic effects on metabolic syndrome (MetS) and its associated complications. Among these complications, peripheral neuropathy is a debilitating condition characterized by nerve damage, often linked to chronic inflammation, oxidative stress, and metabolic dysregulation. Emerging evidence suggests that resveratrol may exert neuroprotective effects by modulating molecular pathways associated with metabolic health. This review focuses on the relationship between resveratrol, Klotho—a protein implicated in longevity and metabolic regulation—and peripheral neuropathy status in individuals with MetS. Klotho acts as a protective factor against oxidative stress and inflammation, processes central to both MetS and neuropathy. Resveratrol has been shown to upregulate Klotho expression in experimental models, suggesting a mechanism by which it may mitigate neuropathic symptoms and improve metabolic parameters. The article explores the mechanistic pathways linking resveratrol to Klotho expression, including the activation of sirtuins, modulation of insulin signaling, and reduction of pro-inflammatory cytokines. Additionally, preclinical and clinical evidence highlighting the effects of resveratrol on nerve function, pain modulation, and metabolic health are reviewed. By synthesizing current knowledge, this review emphasizes the potential of resveratrol as a therapeutic agent targeting both systemic metabolic dysfunction and peripheral neuropathy via Klotho upregulation. The need for further clinical trials to validate these findings and optimize dosing strategies is highlighted, with the ultimate aim of improving outcomes for patients with MetS and neuropathy.