<p>The prevalent engagement of adolescents with social media has prompted speculation regarding its potential impact on well-being. However, existing empirical evidence on the relationship between social media use, especially the academic use of social media, and well-being is anything but conclusive. Further, the cross-cultural generalizability of the relation is under-investigated. To address these issues, this study employed national-representative data from 52 countries/regions (<i>N</i> = 384,061 students) to investigate the relations of both general and academic use of social media with their well-being indicators, including life satisfaction, positive affect, and meaning in life, and examined the cross-cultural generalizability of the relations. Results of multilevel analyses showed that general use of social media had a trivial association with life satisfaction (β = − 0.011) and positive affect (β = 0.038), but not meaning in life (β = − 0.008), after controlling for covariates; academic use of social media had a larger, albeit still small association with life satisfaction (β = 0.052), positive affect (β = 0.074), and meaning in life (β = 0.092). The results are well generalizable across different countries/regions. The theoretical, methodological, and practical implications are discussed.</p>