Rationale: Internalizing problems (i.e., depressive and anxiety symptoms) are known to decrease adolescents' well-being, but knowledge about potential underlying mechanisms is limited. The qualities of adolescents' most proximal relationships with their parents and close friends are expected to play a role in the association between adolescents’ internalizing problems and well-being. Objective: The present study was conducted to 1) investigate the indirect longitudinal association between internalizing problems and adolescents' well-being via the quality of adolescents’ relationships with both their mothers and fathers and their close friends, and 2) test whether our findings were gender invariant. Methods: Data were collected via online questionnaires in two waves at a 12-month interval from adolescents attending three secondary schools in the Netherlands (N = 1298; M age = 13.7 years, 53.2% girls). The data were analyzed using a two-wave cross-lagged panel model in R. Multigroup analyses were performed to examine the gender invariance of the findings. Results: After controlling for baseline levels, results showed that (1) girls, but not boys, who reported more internalizing problems at T1 had lower well-being at T2; (2) girls and boys who reported more internalizing problems at T1 had lower-quality relationships with their mothers, fathers, and close friends at T2; and (3) boys, but not girls, who reported higher-quality friendships at T1 had higher well-being at T2. However, no significant indirect effects between internalizing problems and well-being via the quality of adolescents’ relationships with their parents and close friends were detected. Conclusions: The current study contributes to understanding internalizing problems as an important risk factor to the quality of adolescents' proximal social relationships (parents, friends) and their well-being. The findings support the importance of building high-quality relationships, particularly friendships, and recommend future research to study adolescents’ internalizing problems and well-being including gender-specific examinations.