Health-related quality of life (HRQoL) is defined as a multidimensional subjective assessment of one’s physical and mental health. Homelessness is associated with numerous stressors that can reduce HRQoL. Social support is defined as the availability of individuals, or resources provided by individuals, to cope with stress. Interpersonal social support may be important in buffering HRQoL from the negative implications of stress. Here, we examine this association in a marginalized group known for high rates of physical and mental health comorbidities: adults experiencing homelessness. Participants (N = 581; 63.7% men; Mage = 43.6 ± 12.2) were recruited from homeless-serving agencies in Oklahoma City. Social support was measured with the 12-item Interpersonal Support Evaluation List (ISEL). HRQoL was measured by the Behavioral Risk Factor Surveillance System (BRFSS) survey using self-rated health, the number of poor mental and poor physical health days over the preceding 30 days, as well as the number of limited activity days as the result of poor mental and/or physical health. Perceived stress was assessed using the 4-item Perceived Stress Scale (PSS). The potential moderation effect of social support was examined by assessing the interaction term of social support and stress in a series of linear regression analyses, controlling for sex, age, months homeless, race, education, health insurance status, serious mental illness diagnosis, and recruitment agency/site. There was a significant interaction effect of social support and stress on the prediction of days of poor physical health, days of poor mental health, and days of limited activity (p in all cases ≤ 0.05). Results add to a growing literature on the potentially protective benefits of social support for HRQoL, extend them to a large sample of adults experiencing homelessness in the South, and demonstrate the significance of this moderating effect of social support over and above the influence of several prominent sociodemographic and diagnostic variables. Future work should determine if interventions designed to enhance social support can buffer HRQoL from the deleterious effects of stress among this vulnerable population.