--- - |2+ Abstract Objective Although cancer survival rates continue to improve, overall disparities persist for ethnic minority survivors, who have a disproportionately high risk of experiencing poor quality of life, despite documented higher levels of self‐reported spirituality. Yet little is known about the relationship between spirituality and social support and health outcomes among Hispanic survivors. This study examined (1) differences between Hispanic and non‐Hispanic white survivors on health, social support, and spirituality and (2) the potential mediating roles of mental health and emotional distress on general health perceptions. Methods We analyzed data (N = 7778) from the American Cancer Society's Study of Cancer Survivors‐II, a national cross‐sectional study of adult cancer survivors. Preliminary analysis compared sociodemographic and medical characteristics between the 2 groups to identify significant covariates. Structural equation modeling assessed whether mental health and emotional distress mediate the impact of social support and spirituality on Hispanics' general health perceptions. Results Overall, 693 survivors were Hispanic and 7085 were non‐Hispanic whites. Hispanics reported poorer health and were more likely to have comorbid conditions such as diabetes and depression compared with non‐Hispanic whites. Structural equation modeling indicated that the impact of spirituality on general health perceptions was fully mediated through mental health. Emotional distress did not have a direct effect on general health perceptions nor did it mediate effects of spirituality and social support and on general health perceptions. There was a mediated effect of social support on general health perceptions. Conclusions Spirituality is an important factor in the health of Hispanic survivors. Future studies should explore the impact and effectiveness of spiritual interventions and the beneficial effect for mental health on general health perceptions. - Psycho-Oncology, Volume 27, Issue 9, Page 2189-2197, September 2018.