Obesity and overweight pose significant risks to health, contributing to the prevalence of chronic conditions like type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). The current study aimed to assess the impact of a 6-year nutritional and lifestyle intervention on oxidative and inflammatory markers in individuals aged 55 to 75, specifically those at high risk of CVD. A study was carried out in a group of 80 participants with metabolic syndrome (MetS) residing in Mallorca, Spain, who underwent nutritional intervention based on a low-calorie Mediterranean diet (MedDiet) and promotion of physical activity. Before and after the intervention, several parameters including anthropometric data, haematological factors, blood pressure, and physical activity level were measured. Oxidative and inflammatory biomarkers in plasma were analysed. After the 6-year intervention, participants who managed to reduce their body mass index (BMI) had greater reductions in abdominal obesity, waist to heigh ratio (WHtR), diastolic blood pressure, and glucose levels, and increased high density protein cholesterol (HDL-c) compared to those who did not reduce BMI. This higher reduction in BMI was related to reduced energy intake and increased adherence to MedDiet, with greater polyphenol intake, and total physical activity (PA). Furthermore, improvements in oxidative stress and proinflammatory status were observed in participants who reduced their BMI. Significant reductions in the activity of the prooxidant enzyme, myeloperoxidase (MPO), levels of the lipid oxidation marker, malondialdehyde (MDA), and the proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1,) were found in those who reduced their BMI. In contrast, participants who did not improve their BMI exhibited higher levels of proinflammatory markers such as MCP-1 and tumour necrosis factor α (TNFα), as well as increased activity of the antioxidant enzyme catalase (CAT). Current findings suggest that an effective way to reduce BMI is a hypocaloric MedDiet combined with tailored physical activity to improve oxidative stress and proinflammatory status, and potentially reducing the risk of CVD.