The aim of the present study was to investigate the interrelationships between school-related stress (school performance, teacher interaction), life satisfaction, and depressive symptoms, as well as the potential mediating role of life satisfaction on the association between school-related stress and depressive symptoms. A total of 1,239 adolescents (13–18 years of age) from public elementary and secondary schools in mid-Norway participated in the school-based survey. The data were analysed using structural equations modelling. The present study showed that stress of school performance was significantly and positively related to depressive symptoms and significantly and inversely related to life satisfaction. At the bivariate levels, stress of teacher interaction was associated with more depressive symptoms and reduced life satisfaction. However, these associations were non-significant in the multivariate analyses, controlled for stress of school performance. A significant inverse association was found between life satisfaction and depressive symptoms. Further, life satisfaction partly mediated the association between stress of school performance and depressive symptoms. The results reflect the complexity of the interaction between adolescents’ experience of school performance stress and mental health, and the role of life satisfaction as a potentially relevant mediator of this association.