Background & aim: Quality of life of patients with type 2 diabetes is one of the most important indicators of physical and mental health in these people. The aim of this study was to determine the structural pattern of health-related quality of life in patients with type 2 diabetes based on health-related literacy and self-efficacy by considering the mediating role of self-care activity. Methods: The present study was a correlational study using path analysis method performed on 300 patients with type 2 diabetes referred to public and private medical centers in Tehran and Mashhad. Samples were selected using available sampling method and questionnaires of Quality of Life (SF-36), Health Literacy (HLS), Diabetes-Related Self-Efficacy (DMSES) and Diabetes Self-Care Activities (SDSCA) were completed by them. Data were analyzed using descriptive statistics (central and dispersion indices) and inferential (Pearson correlation) using SPSS-25 and LISREL 8. 80 software. Results: The results of Pearson correlation test indicated that health literacy, diabetes-related self-efficacy, and self-care activities were significantly (p≤ 0. 05) correlated to health-related quality of life. Furthermore, the results of path analysis revealed that diabetes-related health literacy and self-efficacy had no direct effects on health-related quality of life, but had a significant indirect effect on the quality of health-related life of type 2 diabetes patients through self-care activities. Conclusion: The results showed that the quality of life of patients with type 2 diabetes can be predicted based on health literacy and self-efficacy and also self-care exerts its effect through a mediating role. Health literacy and self-efficacy can play an effective role in improving and also predicting the quality of life of patients with type 2 diabetes. Also, self-care activities are important factors in patients with type 2 diabetes. In addition, engaging in self-care activities can help reduce the psychological symptoms of diabetes in patients with diabetes, which can ultimately improve the quality of life of patients with diabetes. Physicians and psychotherapists can improve the health literacy and self-efficacy of patients with diabetes to increase their quality of life.