Background and Aims: The purpose of this study was to identify the role of neuroticism and psychological flexibility (PF) in quality of life (QOL) and chronic fatigue (CF) in patients with Type 2 Diabetes Mellitus (T2DM). Materials and Methods: We considered the all of the patients with T2DM over aged 30 years and living in the province of Hamadan, Iran in 2014 that were referred to the Hamadan Diabetes Center. A sample size of 170 patients was selected by the simple random sampling method. The measuring tools were completed by the patients. To test assumptions, the Pearson correlation and structural equation modeling were used. Results: The results showed that the correlation coefficient between neuroticism, with CF (r=0.579; p<0.001) and QOL (r=-0.242; p<0.001), and also correlation between PF and CF (r=0.287; p<0.001) are significant. There is no significant relationship between QOL and PF (r= -0.098; p=0.203). Structural equation modeling showed that neuroticism has a direct positive effect in CF (p<0.001) and a negative effect on QOL (p<0.001), and the PF has a significant direct effect on CF (p=0.014) and an indirect effect on QOL. The CF affects negatively on the QOL (p<0.001). Conclusion: It could be concluded that neuroticism and PF play important roles in QOL and CF and with effective intervention can help patients with diabetes to improve them QOL.