Objective: To explore effects of comprehensive nursing intervention based on empowerment principle on medication compliance and self-efficacy in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 120 newly diagnosed T2DM patients who were treated in endocrine clinic of the hospital from February 2017 to April 2019 were enrolled. They were divided into an observation group (n=60) and a control group (n=60) according to random number table method. The control group was given traditional nursing intervention, while the observation group was given comprehensive nursing intervention based on empowerment principle. The medication compliance, diabetes metabolic indexes, self-care behaviors, self-efficacy and quality of life before and after intervention were compared between the 2 groups. Results: The good rate of medication compliance in the observation group was higher than that in the control group (93.33% vs 80.00%) (P<0.05). After 3 and 6 months of intervention, fasting blood glucose (FPG), 2 h postprandial blood glucose (2hPG) and glycated hemoglobin (HbA1c) in the observation group were lower than those in the control group (P<0.05). After 1 , 3 and 6 months of intervention, scores of Summary of Diabetes Self-Care Activities (SDSCA) in the observation group were higher than those in the control group (P<0.05), scores of diabetes self-efficacy scale (DSES) were higher than those in the control group (P<0.05), and scores of World Health Organization Quality of Life-Brief Version (WHO QOL-BREF) were higher than those in the control group (P<0.05). Conclusion: Comprehensive nursing intervention based on empowerment principle can improve medication compliance, improve diabetes metabolic indexes, improve self-care ability, self-efficacy and quality of life in T2DM patients.