The purpose of this study was to assess the extent to which self-esteem and depressive symptoms mediated the influence of stigma on life satisfaction among out-of-school youth in the Republic of Korea. Cross-sectional data were collected from 318 youth, aged 18 to 23 years (20.67 ± 1.12), who provided information on perceived stigma, self-esteem, depressive symptoms, life satisfaction, and personal characteristics. A hierarchical linear regression analysis was followed by a path analysis to investigate the mediation effects. Stigma was found to be negatively associated with life satisfaction. Self-esteem mediated the negative association between stigma and life satisfaction, while depressive symptoms mediated the positive association between stigma and life satisfaction. The path analysis results showed that the influence of depressive symptoms on life satisfaction had the largest path coefficient (β = −0.60, p < .01) and the influence of self-esteem on life satisfaction also has a large path coefficient (β = 0.52, p < .01). This study demonstrated that self-esteem and depressive symptoms are important to the relationship between stigma and life satisfaction. Implications are discussed regarding possible stigma-reduction strategies and interventions to help out-of-school youth integrate into society and lead successful and satisfying lives.