The objective of this study was to prospectively examine the association between leisure-time physical activity and risk of disability pension, as well as risk of disability pension because of musculoskeletal or mental disorders in a large population-based cohort. Data on participants aged 20–65 years in the Norwegian Nord-Trφndelag Health Study 1995–1997 (HUNT2) were linked to the National Insurance Database. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for disability pension across physical activity categories. During a follow-up of 9.3 years and 235 657 person-years, 1266 of 13 823 men (9%) and 1734 of 14 531 women (12%) received disability pension. Compared with individuals in the inactive group, those in the highly active group had a 50% lower risk of receiving disability pension (HR for men: 0.50, 0.40–0.64; women: 0.50, 0.39–0.63). After comprehensive adjustment for potential confounders, the risk remained 32–35% lower (HR for men: 0.68, 0.53–0.86; women: 0.65, 0.51–0.83). The associations were stronger for disability pension due to musculoskeletal disorders than mental disorders. In summary, we observed strong inverse associations between leisure-time physical activity and disability pension. Our findings strengthen the hypothesis that leisure-time physical activity may be important for occupational health in reducing disability pension.