Aims <p>Physical activity and sedentary behaviour are major modifiable risk factors for cardiovascular disease. However, the effect of leisure-time physical activity, particularly moderate-to-vigorous leisure-time physical activity, on the development of cardiovascular disease remains unclear. This study aimed to investigate the potential mediating role of white blood cell (WBC) count in the associations among moderate-to-vigorous leisure-time physical activity, sedentary behaviour, and cardiovascular disease.</p> Methods <p>We assessed the data of 11,355 participants from the National Health and Nutrition Examination Survey between 2013 and 2018. multivariable logistic regression analyses were conducted to determine the associations of moderate-to-vigorous leisure-time physical activity and sedentary behaviour with cardiovascular disease. Subgroup mediation analyses were performed to identify potential modifying factors such as age, WBC count, and triglyceride-glucose index.</p> Results <p>After adjusting for demographic, lifestyle, and clinical covariates, our analyses revealed a significant negative association between moderate-to-vigorous leisure-time physical activity and cardiovascular disease, while sedentary behaviour (&gt; 7.5&#xa0;h/day) showed no significant association, with odds ratios close to 1. Furthermore, the results from our subgroup mediation analyses suggested that WBC count partially mediated these associations, particularly in participants aged 41–59 years and those within the triglyceride-glucose index range of 6.719–8.684.</p> Conclusions <p>These findings provide insight into the inflammatory mechanisms that link moderate-to-vigorous leisure-time physical activity and sedentary behaviour with reduced cardiovascular disease risk.</p>