Background: Whether large body size increases multiple sclerosis (MS) risk in men is not well understood. Concurrently, physical exercise could be an independent protective factor. Objective: To prospectively investigate the association between body mass index (BMI) and aerobic fitness, indicators of body size and exercise, and MS risk in men. Methods: We performed a population-based nested case-control study within the historical cohort of all Norwegian men, born in 1950–1975, undergoing mandatory conscription at the age of 19 years. 1016 cases were identified through linkage to the Norwegian MS registry, while 19,230 controls were randomly selected from the cohort. We estimated the effect of BMI and fitness at conscription on MS risk using Cox regression. Results: Higher BMI (≥25 vs 18.5–<25 kg/m²) was significantly associated with increased MS risk (adjusted relative risk (RR_adj) = 1.36, 95% confidence interval (CI): 1.05–1.76). We also found a significant inverse association between aerobic fitness (high vs low) and MS risk independent of BMI (RR_adj = 0.69, 95% CI: 0.55–0.88, p-trend = 0.003), remaining similar when men with MS onset within 10 years from conscription were excluded ( p-trend = 0.03). Conclusion: These findings add weight to evidence linking being overweight to an increased MS risk in men. Furthermore, they suggest that exercise may be an additional modifiable protective factor for MS.