Psychological problems commonly experienced by patients with type 2 diabetes mellitus (T2DM) cause diabetes fatigue conditions that can further worsen the treatment prognosis. We conducted this investigation to determine the effectiveness of a resilience-based Islamic program on diabetes fatigue and health-related quality of life (HRQoL) by measuring the biochemical indicators of T2DM. This was a quasi-experimental study performed from May to August 2021, in which 80 respondents aged 18-64 years diagnosed with T2DM were included through purposive sampling at a male:female sex ratio of 1:1 in the control group and 17:23 in the treatment group. A resilience-based Islamic program (a combination of stress management, mindfulness, prayer, and dhikr (the ritual formula of Sufi brotherhood recited devotionally in praise of Allah and as a means of attaining ecstatic experience)) was implemented in the treatment group for six sessions by blended online and offline interventions. Multidimensional Fatigue Inventory-20 and World Health Organization Quality of Life, Brief Form were used to evaluate diabetes fatigue and HRQoL. Blood tests were performed to measure HbA1c, total antioxidant serum, insulin, cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) levels from baseline to 3 months. Statistical analyses were conducted using paired t test, Wilcoxon signed-rank test, independent t test, and Mann-Whitney U test. The resilience-based Islamic program had a beneficial impact on the levels of HbA1c (p < 0.001), lipid profile (triglyceride) (p = 0.011), HDL-c (p = 0.01), LDL-c (p < 0.001), total antioxidant serum (p = 0.001), insulin (p < 0.001), diabetes fatigue (p < 0.05), and HRQoL (p < 0.05) in patients of the treatment group. The results of biochemical tests related to T2DM also indicated a reduction in diabetes fatigue and an increase in HRQoL due to the resilience-based Islamic program. Considering that a patient's resilience to diabetes is an important factor in the management of diabetes fatigue, the resilience-based Islamic program can be applied at public health centers and community levels to increase T2DM resilience.