Introduction. Diabetes is a major public health problem. Little is known about the spiritual well-being and its relationship with quality of life (QOL) in Iranian Muslim patients with diabetes. This study investigated the spiritual well-being and QOL of Iranian adults with type 2 diabetes and the association between spiritual well-being, QOL, and depression. Methods. A cross-sectional study was done among 203 patients with type 2 diabetes mellitus in Isfahan, Iran. Quality of life and spiritual well-being were measured using the functional assessment of chronic illness therapy-spiritual well-being (FACIT-Sp). Depression was assessed using the Patient Health Questionnaire-2 (PHQ-2). Descriptive analysis, Pearson's correlation, and multiple regression analysis were performed for statistical assessment. Results. The mean QOL was 61.00 (SD = 9.97) and the mean spiritual well-being was 30.59 (SD = 6.14). Sixty-four percent of our studied population had depressive disorders. There was a significant positive correlation between all QOL subscales and meaning, peace, and total spiritual well-being score. Conclusion. The results of this study showed poor QOL and spiritual well-being and high prevalence of depression in Iranian patients with type 2 diabetes compared to other studies' findings especially western studies. This indicates the need for psychosocial and spiritual support in caring for Iranian patients with diabetes.