〔Abstract〕 Objective To investigate the therapeutic effect of repaglinide combined with metformin on type 2 diabetes mellitus (T2DM). Methods A total of 57 T2DM patients admitted to Quanzhou First Hospital affiliated to Fujian Medical University from March 2020 to March 2021 were randomly divided into a control group and an observation group according to random number table method. Control group 28 patients received metformin treatment; Observation group 29 patients received repaglinide combined with metformin treatment. The therapeutic effects of the two groups were compared. Results After treatment, fasting blood glucose (FPG), 2h postprandial blood glucose (2h PG), glycosylated hemoglobin (HbA1c) and mean amplitude of plasma glucose excursions (MAGE) levels in the two groups were lower than before, and the observation group was lower than that in the control group, the differences were statistically significant (P < 0.05). The levels of serum oxidative stress in patients of the two groups were better than those before treatment, the differences were statistically significant (P < 0.05), and the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), 6-keto-prolandin F-1A (6-Keto-PGF-1a) in the observation group were higher than those in the control group. The levels of 8-isoprostanes2a (8-iso-PGF2a) and malondialdehyde (MDA) were lower than those of the control group, and the differences were statistically significant (P < 0.05). The total effective rate of the observation group was higher than that in the control group, and the difference was statistically significant (P < 0.05). There was no statistical significance in the occurrence of adverse reactions between the two groups (P > 0.05). Conclusion Repaglinide combined with metformin in the treatment of T2DM has a better effect, which can effectively control patients' blood glucose level and regulate the oxidative stress response, with high safety.