<p>Although studies have tried to explore the relationship between problematic mobile phone use and depressive symptoms in adolescents, most of them are limited to relatively simple correlations, and the mechanism needs to be further explored, particularly in China. To address this gap, guided by the social ecological theory and the stress-buffering model, this study estimated the mediating role of school connectedness and the moderating role of family function in the relationship between problematic mobile phone use and depressive symptoms in the Chinese cultural context. A total of 402 Chinese adolescents (68.16% girls, <i>M</i>_age = 16.34, SD = 0.70 at baseline) completed self-reported depressive symptoms, problematic mobile phone use, school connectedness, and family functioning at two time points with 6-month intervals. Descriptive statistics, cross-lagged panel analysis, half-longitudinal mediation effects analysis, and moderation analysis were estimated in the present study. Problematic mobile phone use exacerbated depressive symptoms and vice versa. School connectedness partially mediates the path that problematic mobile phone use influences depressive symptoms, not vice versa. Moreover, the association between problematic mobile phone use and school connectedness, as well as the association between school connectedness and depressive symptoms, is moderated by family functioning. We observed similar associations in rural and urban adolescents. The findings contribute significantly to revealing the complex mechanisms between problematic mobile phone use and depressive symptoms. Enhancing school connectedness and increasing family functioning should be applied in interventions for the prevention and intervention of depressive symptoms among adolescents.</p>