Abstract Background Poor mental health remains the leading cause of disability, with considerable negative impacts in low- and middle-income countries. In this study, we examined the prevalence and correlates of psychosocial distress among in-school adolescents in Mozambique. Methods This was a cross-sectional study of 1918 in-school adolescents, using data from the 2015 Mozambique Global School-Based Health Survey. Descriptive and inferential statistics were adopted in analysing the data. Statistical significance was set at p < 0.05. Results The prevalence of psychosocial distress was 21.2% (24.1% females and 18.5% males). Older adolescents [AOR = 1.681, 95% CI = 1.233–2.292] had higher odds of experiencing psychosocial distress, compared with younger adolescents. In terms of sex, males [AOR = 0.755, 95% CI 0.601–0.950] had lower odds of experiencing psychosocial distress, compared with females. Adolescents who were bullied [AOR = 1.451, 95% CI 1.150–1.831], physically attacked [AOR = 1.802, 95% CI 1.404–2.313], and engaged in a physical fight [AOR = 1.376, 95% CI 1.070–1.769] were respectively more likely to experience psychosocial distress than those who did not. Conversely, adolescents who had close friends [AOR = 0.503, 95% CI 0.372–0.681] had lower odds of being psychosocially distressed than those who did not have close friends. Conclusion The prevalence of psychosocial distress among in-school adolescents in Mozambique is relatively high. The country may not be able to meet the Sustainable Development Goal 3.4 target of promoting mental health and wellbeing of all by the year 2030 if current rates of psychosocial distress persist among in-school adolescents. Mental health education and counselling as well as social support from friends should be intensified to reduce mental health problems and enable adolescents to effectively deal with the psychosocial challenges encountered in their transition from childhood to adulthood.