BACKGROUND: Both insufficient physical activity (PA) and excess body weight are important risk factors for cardiovascular disease (CVD), and PA is closely related to body weight. However, it remains unclear whether PA modifies or mediates the association of body mass index (BMI) with CVD. METHODS: We conducted a cross-sectional study of 35,406 adults participating in the National Health and Nutrition Examination Survey (NHANES). The mediation and interaction effects of PA were assessed using a four-way decomposition approach. An additional two-step Mendelian randomization (MR) analysis was performed to verify the potential causal mediation effect. RESULTS: A strong association was observed between PA and lower odds of CVD after adjusting for all confounders [Odds Ratio (OR): 0.84
95% Confidence Interval (CI): 0.74-0.95]. Increased BMI was associated with higher odds of CVD (OR: 1.04
95% CI: 1.03-1.04). PA showed interaction and mediation effects on the association of BMI with CVD. The overall proportion attributable to interaction was -37.5%, while the overall proportion attributable to mediation was 22.2%. MR analysis further confirmed that PA causally mediated the pathway from BMI to CVD. CONCLUSIONS: PA modified the association of BMI with CVD, suggesting that sufficient PA is needed to lower the impact of high BMI on CVD risk. Moreover, we found that PA served as a causal influence on the association of BMI with CVD, indicating that higher BMI led to a lower level of PA, which in turn increased the risk of CVD.