Obesity and overweight are disorders with high impact on the morbidity and mortality of chronic diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). We aim to assess the effects of 2-year nutritional and lifestyle intervention on oxidative and inflammatory status in individuals of 55 years of age and over at high CVD risk. Participants (n = 100 individuals of 55 years of age and over living in the Balearic Islands, Spain) were randomized into control and intervention group. Anthropometric and haematological parameters, blood pressure and physical activity were measured before and after the intervention. Oxidative and inflammatory biomarkers in plasma, urine, peripheral blood mononuclear cells (PBMCs) and neutrophils were determined. A higher reduction in abdominal obesity, blood pressure and triglycerides levels was observed after a 2-year intervention. An improvement of oxidative stress and proinflammatory status was demonstrated with a significant reduction in myeloperoxidase, xanthine oxidase, malondialdehyde and monocyte chemoattractant protein-1 (MCP1) levels, and an increase in polyphenols in plasma was observed. A decrease in reactive oxygen species production in PBMCs and neutrophils levels after zymosan and lipopolysaccharide activation was found in the intervention group with respect to the control group. The intervention with hypocaloric Mediterranean Diet and customized physical activity improves oxidative stress and proinflammatory status and could contribute to decreasing the CVD risk.