Purpose: The study aims to evaluate the mediating effect of depressive symptoms on the relationship between physical symptoms and health-related quality of life (HRQOL) in hematopoietic stem cell transplant (HSCT) survivors and to test a conceptual model of psychosocial factors, in addition to physical and psychological symptoms, that might contribute to HRQOL.Methods: This is a secondary data analysis using HSCT survivors (N = 662) identified from the Center for International Blood and Marrow Transplant Research. Data were collected through mail and phone surveys and medical records. We used structural equation modeling to test the mediating role of depressive symptoms on the relationship of physical symptoms with HRQOL. We also tested comprehensive pathways from physical symptoms to HRQOL by adding psychosocial factors (optimism, coping, and social constraints).Results: In the depressive symptom mediation analyses, physical symptoms had a stronger direct effect on physical HRQOL (b = −0.98, p < 0.001) than depressive symptoms (b = 0.23, p > 0.05). Depressive symptoms were associated with mental HRQOL and mediated the relationship between physical symptoms and mental HRQOL. In comprehensive pathways, physical symptoms remained the most significant factor associated with physical HRQOL. In contrast, depressive symptoms had direct effects (b = −0.76, p < 0.001) on mental HRQOL and were a significant mediator. Psychosocial factors were directly associated with mental HRQOL and indirectly associated with mental HRQOL through depressive symptoms.Conclusion: Physical symptoms are most strongly associated with physical HRQOL, while depressive symptoms and psychosocial factors impact mental HRQOL more than physical HRQOL. Interventions addressing psychosocial factors as well as symptoms may improve the HRQOL of HSCT survivors.