Objective To assess health status of rural residents at high risk for chronic disease and to explore the relationship between health literacy and health outcomes. Methods Rural residents at high risk for chronic disease were selected from 5 villages of 19 service centers served by the School of Nursing, Guangzhou University of Chinese Medicine, using random and convenience sampling. The Health Literacy Scale for Patients with Chronic Diseases, General Self-Efficacy Scale, and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were employed to evaluate health literacy and health outcomes of the rural residents. Structural equation model was used to examine the relationships among variables. Results The sample scored 93.5±15.4 on health literacy, and self-efficacy score was significantly lower than the national norm (P＜0.01). Scores of 7 domains of the SF-36 except physical role were significantly lower than national general population (P＜0.01 for all).Compared with national norms of chronic patients, the scores of physical function, physical role, general health and vitality were significantly higher, while the scores of bodily pain and mental health were significantly lower in rural residents at high risk for chronic disease (P＜0.05,P＜0.01).Structural equation model showed that higher health literacy was related to higher self-efficacy and better quality of life （P＜0.01). Self-efficacy mediated the relationship between health literacy and quality of life (P＜0.05). Conclusion Health literacy, self-efficacy, and quality of life of rural residents at high risk for chronic disease need to be improved. Improving health literacy may contribute to enhancing health outcomes.