Systematic screening for depression among adolescents and young adults living with HIV (AYALHIV) is limited or nonexistent in some settings in sub-Saharan Africa due to the lack of integration of mental healthcare into HIV program. This can increase the risk of suicidal thoughts and cause emotional distress, which can have an adverse effect on their treatment outcomes. Establishing evidence of the burden of depression among AYALHIV is key for advocacy for systematic screening. This study examined the burden of depressive symptoms and associated factors among AYALHIV in Ghana. A single-center facility-based cross-sectional study was conducted among AYALHIV at the Infectious Disease Center of the Korle Bu Teaching Hospital, Accra, Ghana, from May 2023 to March 2024. Depressive symptoms were assessed through the administration of the Patient Health Questionnaire for Adolescents (PHQ-A). The prevalence of depressive symptoms (PHQ-A score ≥ 5) and associated factors was examined using logistic regression. A total of 280 AYALHIV were recruited with 50.7% being female. Sixty percent were young adults, and the rest were adolescents. About 75% were virally suppressed. The prevalence of depressive symptoms was 40.7% (95% CI: 34.9%-46.7%). Being an orphan (adjusted odds ratio [aOR] = 2.6, 95% confidence interval [95% CI]: 1.2-5.6), female (aOR = 1.8, 95% CI 1.1-3.0), and having high perceived stigma (aOR = 2.2, 95% CI: 1.3-3.7) were associated with having depressive symptoms. Viral nonsuppression was associated with depressive symptoms but likely through its association with HIV stigma. Depressive symptom burden was high among AYALHIV despite viral suppression in the majority of them. There is a need for the design of mental health screening integration into youth-centered HIV programs based on context for early identification, counseling, and treatment of mental health challenges to ensure good quality of life and avert other mental health challenges.