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To investigate the association of social isolation with physical activity and leisure-time sedentary behavior among adolescents. We used data from the Global School-based Health Survey, including a representative sample of 296,861 adolescents (11-18y) from 79 countries (48.9% girls, 14.5 ± 1.6 years). Social isolation was estimated by combining the self-reported number of friends and loneliness perception. Physical activity and leisure-time sedentary behavior were assessed through questionnaires. Multinomial logistic regression models were created to analyze the associations of social isolation with physical activity and leisure-time sedentary behavior. Compared with those practicing ≥60 min of physical activity during 1‐4 days/week, social isolation was associated with a higher prevalence of not practicing physical activity (Prevalence ratio [PR]:1.24; 95%CI:1.19–1.29), and a lower prevalence of practicing during ≥5d/wk. (PR:0.91; 95%CI:0.88–0.94). Compared with <4 h/d of leisure-time sedentary behavior, being socially isolated was also associated with a higher prevalence of 4-7 h/d (PR: 1.08; 95%CI:1.03–1.14) and ≥ 8 h/d (PR: 1.24; 95%CI:1.16–1.33) of leisure-time sedentary behavior. Compared with those participants without elevated leisure-time sedentary behavior and with those practicing adequate physical activity, social isolation was independently associated with a higher prevalence of physical inactivity (PR: 1.20; 95%CI: 1.15–1.26) and elevated leisure-time sedentary behavior (PR: 1.21; 95%CI: 1.14–1.30), as well as with both risk factors simultaneously (PR: 1.36; 95%CI: 1.28–1.45). Reducing social isolation could be an important component of future interventions to reduce sedentary behavior and physical inactivity among adolescents. • Social isolation was associated with lower moderate-to-vigorous physical activity. • Social isolation was associated with a higher leisure-time sedentary behavior. • Social isolation was associated with the combination of lower PA and higher SB. [ABSTRACT FROM AUTHOR]