In contemporary society, one of the most pressing concerns is the prevention and treatment of chronic diseases (CDs). CDs are non-communicable diseases with persistent effects; they include cardiovascular diseases (CVDs), neurodegenerative diseases, cancer, and diabetes, among others. Despite their high prevalence, epidemiological studies indicate that 30% of cancers, 80% of cardiovascular diseases, and 90% of type 2 diabetes could be avoided by diet and lifestyle changes. Furthermore, several studies have shown the strong association between an excess of oxidative stress, driven by reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the pathogenesis of CDs. Prolonged exposure to elevated levels of pro-oxidant factors has been linked to functional impairments in enzymes and cellular structures, which in turn lead to aberrant gene expression. Consequently, the integration of antioxidant compounds into the diet has been proposed as a preventive strategy to mitigate oxidative stress and thereby reduce the incidence of CDs. For instance, resveratrol, found in red grapes and berries, activates the SIRT1 gene, improving mitochondrial function and reducing oxidative damage, which helps prevent atherosclerosis and lowers CVD risk. Similarly, epigallocatechin gallates (EGCG) in green tea reduce oxidative stress and inflammation in adipose tissue by modulating the UCP1 gene, promoting thermogenesis and preventing obesity-related complications. Therefore, implementing dietary interventions is expected to reverse the oxidative imbalance that favors the development of these diseases by combining a preventive dietary approach with therapeutic intervention. In this sense, nutrigenomics aims to serve as a key tool by determining the influence of diet on gene expression and, in particular, by identifying how the intake of antioxidant compounds can modify the oxidative stress produced. This review aims to provide a general vision on the role of antioxidants in the prevention of chronic diseases, incorporating nutrigenomics as a valuable tool.