Background: In sub-Saharan Africa (SSA), adolescent girls and young women are three times more likely than boys to have depressive disorders. Understanding adolescents’ unique and common vulnerabilities and protective factors is essential for the development of appropriate interventions and programming focused on child and adolescent mental health. This paper examines the prevalence and predictors of depressive symptoms among high school adolescent girls in southern Uganda. Methods: Baseline data from a longitudinal cluster randomized study involving 1260 adolescent girls (14–17 years), recruited from 47 secondary schools were utilized. Depressive symptoms were estimated using the 21-item Beck’s Depression Inventory. Hierarchical linear regression modelling was utilized to estimate key predictors of depressive symptoms among adolescent girls. Results: Of the total sample, 16.35% (n=206) reported severe depressive symptoms and almost one in every three adolescent girls interviewed (29.68%, n=374) reported moderate symptoms. These symptoms were more prevalent among older adolescents (16 years and above). In addition, family relationships, social support, as well as measures of psychological wellbeing (self-concept and self-esteem) were all associated with lower levels of depressive symptoms. Hopelessness was associated with higher levels of depressive symptoms among adolescent girls. Conclusion: Findings from this study indicate a high prevalence of depressive symptoms, especially among older adolescent girls. In addition, family support factors and adolescents’ psychological wellbeing were associated with low levels of depressive symptoms –pointing to the need to strengthen family functioning and adolescent’s psychological wellbeing to mitigate risks. Taken together, findings support increasing calls for early screening and detection of depressive symptoms to facilitate timely referral to care and treatment. Findings may also inform the development and incorporation of gender-specific mental health components in programming targeting adolescent girls, in low-resource communities in SSA.Trial Registration: This trial was prospectively registered with ClinicalTrials.gov (registrationnumber: NCT03307226) on 11 October 2017.