Objective: The current study sought to investigate the association between HIV-related stigma, self-esteem, social support, and depression of people living with HIV and AIDS (PLWHA) in Namibia. Method: Purposive sampling was used to recruit a total of 124 men and women living with HIV/AIDS in the Katima Mulilo region of northern Namibia. A cross-sectional survey was used to collect information on demographics, self-esteem, social support, HIV-related stigma, and depression. Results: Correlation analysis revealed that HIV-related stigma, self-esteem, and social support were all significantly correlated with depression. Further, Ordinary Least Squares (OLS) regression analysis indicated that HIV-related stigma was the largest risk factor and self-esteem was the largest protective factor with respect to depressive symptoms. Discussion: Findings indicated the necessity of appropriate assessment and intervention for psychosocial distress among PLWHA. Helping professionals should design evidence-based interventions that address individual and societal challenges that impact people living with HIV and AIDS.