Although many studies have investigated the impact of HIV on cognitive, physical, academic, and psychosocial functioning, little is known about the self-perception of health-related quality of life (HRQOL), subjective well-being (SWB), social-emotional well-being, and psychopathology risks of adolescents with HIV. This study aimed to address gaps in the literature by exploring the psychosocial outcomes of adolescents with HIV from a strength-based assessment approach, as opposed to a traditional deficit-based approach. Specifically, we explored the relationship between HRQOL, SWB, social-emotional strengths, and psychopathology symptoms to develop a more comprehensive understanding of the physical and psychological well-being of adolescents with HIV (n = 42) compared to a community-based sample (n = 42) in the Southeastern US. Participants completed self-report measures, and data were analyzed for significant correlations, group differences between adolescents with HIV and a community-based sample, and social-emotional predictors of physical functioning and SWB. For adolescents with HIV, several HRQOL indicators were positively correlated with life satisfaction and social-emotional strengths indicators and negatively correlated with negative affect and psychopathology symptoms. Additionally, there was a significant main effect of parents' marital status on participants' perceptions of their social functioning and psychopathology symptoms. When differences in parents' marital status were controlled for, the overall mean ratings of participants' HRQOL, SWB, social-emotional strengths, and psychopathology risks did not significantly differ between groups. Furthermore, parents' marital status and self-rated empathy skills significantly predicted physical functioning of adolescents with HIV, but no significant or meaningful variables were found to predict their SWB. These findings highlight the need for further research on the use of a comprehensive assessment framework to enhance our understanding of the overall well-being of adolescents with HIV.