Although antiretroviral treatment (ART) access has been universal in recent years, few studies have examined if this policy contributes to the mental health of the patients. This study assessed depression and its relations with health-related quality of life (HRQOL), which is defined as the status of general well-being, physical, emotional, and psychological, among HIV patients. A cross-sectional study was conducted in 482 patients at five outpatient clinics. Patient Health Questionnaire-9 (PHQ-9) and EuroQol-5 dimensions-5 levels (EQ-5D-5L) were used to assess the severity of depression and HRQOL. About one-fifth of patients reported symptoms of depression. According to the result of a multivariate logistic regression model, patients who had a lower number of CD4 cells at the start of ART, who received ART in the clinic without HIV counseling and testing (HCT) services, who had a physical health problem, and who experienced discrimination were more likely to have depression. Depression was associated with significantly decreased HRQOL. Depression is prevalent and significantly negatively associated with HRQOL of HIV/AIDS patients. We recommend screening for depression and intervening in the lives of depressed individuals with respect to those who start ART late, and we also recommend community-based behavioral change campaigns to reduce HIV discrimination.