The trajectory of multiple sclerosis (MS) is shaped by complex interactions between genetic susceptibility and environmental factors. This review examines modifiable non-infectious determinants across the life course and proposes integrated prevention strategies. Key factors include vitamin D deficiency, low UV exposure, smoking, adolescent obesity, air pollution, and chemical environmental exposures. Mendelian randomization studies support the causality of several determinants, particularly low vitamin D and high BMI. Adolescence emerges as a critical susceptibility window where the maturing immune system is uniquely sensitive to metabolic and environmental triggers. Among validated interventions, vitamin D supplementation stands out for its ability to reduce disease activity in early MS. Effective prevention requires both individual actions and structural public health policies, such as air quality regulations and urban “walkability”. Future efforts should prioritize multimodal strategies targeting high-risk youths through the educational system (physical activity, weight management, and smoking prevention). These holistic approaches offer broad-spectrum benefits, reducing the burden of MS while preventing comorbidities, including cardiovascular, metabolic but also cancer.