Diabetes, obesity, and cardiovascular disease (CVD) represent an escalating global health challenge, contributing significantly to morbidity, mortality, and healthcare costs. Evidence from large cohort studies and clinical trials underscores the impact of diabetes and obesity as major risk factors for CVD, causing systemic inflammation, insulin resistance, and neurohormonal activation. Frequently, a sedentary lifestyle and unbalanced dietary habits are associated with these risk factors. Physical activity and exercise training interventions, a Mediterranean and plant-based diet, smoking cessation, and reduction of alcohol have shown promise in mitigating these risks. The implementation of lifestyle and pharmacotherapy have emerged as new pillars of preventive medicine. This review discusses the evidence of lifestyle interventions to reduce the burden of diabetes, obesity, and CVD. It is highlighted that only a multifaceted, sustained approach integrating lifestyle interventions and pharmacological strategies can reduce the burden of disease and improve long-term outcomes.