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Participation in leisure and social activities (LSA) is associated with better health outcomes and lower mortality. Previous observational studies demonstrated a relationship between engagement in LSA and both mental and physical health. Although several studies examined the association between LSA and health outcomes, including cardiovascular disease, their possible causal relationship has not been studied. In this study, we investigated the causal relationship between LSA and various health outcomes, including cardiovascular disease, using data from genome-wide association study summary statistics (sample size = 63,926-1,557,411) and a Mendelian randomization approach. Genetically predicted LSA were associated with a reduced risk of several health outcomes, including coronary artery disease and coronary atherosclerosis. Mediation analysis indicated that these effects were partly mediated by modifiable risk factors, such as body mass index, smoking and lipid levels. These findings highlight the importance of LSA in disease prevention and health promotion.