Purpose: Promoting the health-related quality of life (HRQOL) is an important aim of nursing care for immigrant women. The aim of this study was to evaluate the level of HRQOL and its relationships with social support, acculturative stress, and depression among Vietnamese immigrant women. Method: A total of 216 Vietnamese immigrant women residing in South Korea participated in the study. Participants completed a series of questionnaires, including measures of social support, acculturative stress, depression, and HRQOL. For statistical analyses, a path analysis was applied. Results: Social support, acculturative stress, depression, and HRQOL were interrelated. Acculturative stress and depression directly influenced the mental health component of HRQOL, whereas social support indirectly influenced HRQOL through acculturative stress and depression. Only depression directly influenced the physical health component of HRQOL. Conclusion: Results suggest that social support and acculturative stress are related factors in preventing depression and promoting HRQOL, especially mental health, among Vietnamese immigrant women.