Background: Diabetes is one of the most common diseases in the world. The most important underlying cause of death in diabetic patients is the lack of self-care and management. However, there is little known about the influence of coping strategies and spiritual well-being (SWB) on self-care in diabetic patients. Aims: This study aimed to investigate the relationship between self-care activities with coping strategies and spiritual well-being (SWB) in patients with type 2 diabetes mellitus (T2DM). Methods: In this descriptive–analytical study, we selected 236 patients with T2DM referred to the diabetes hospital clinics in the southwest of Iran. Inclusion criteria were patients diagnosed with T2DM, with the age group ranging 20–80 years, literate, not suffering from severe and debilitating complications of diabetes and lacking acute psychological illness. Exclusion criteria included refusing to complete questionnaires and cognitive or emotional impairment. Instruments include the demographic questionnaire, Summary of Diabetes Self-Care Activities, Lazarus and Folkman’s Coping Strategies Questionnaire and the Spiritual Well-Being Scale (SWBS; developed by Paloutzian and Ellison). To examine the relationship between variables, the Pearson correlation and multiple stepwise regression analysis were used. Results: The findings of this study on 236 patients with T2DM (53.25 ± 10.91) including 76 (32.2%) males and 160 (67.8%) females showed the majority of participants were female, the age group was between 41 and 60 years (68.22%), had a Diploma (63.98%), were insured (63.55%) and had a moderate economic situation (55.93%). There was a direct and significant correlation between self-care activities and coping strategies ( r = 0.163, p < 0.05), and only a problem-focused coping strategy was considered as a predictor variable of self-care ( p < 0.01). There was a direct and significant correlation between self-care and SWB ( r = 0.385, p < 0.01). Conclusion: The results of this study showed that there is a significant relationship between self-care and the problem-focused dimension of coping strategies and SWB in patients with T2DM.