Objective: To investigate the effects of glipizide combined with metformin on blood glucose levels and pancreatic beta-cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Methods: A total of 102 patients with newly diagnosed T2DM admitted to the hospital from April 2024 to April 2025 were selected as subjects. Using a random number table, they were divided into the combination group and the metformin group, with 51 patients in each group. Patients in the metformin group were treated with metformin, while those in the combination group were treated with glipizide combined with metformin. Both groups were treated for 3 months. Blood glucose levels, fasting C-peptide, 2-hour postprandial C-peptide, homeostasis model assessment-beta (HOMA-beta), homeostasis model assessment of insulin resistance (HOMA-IR), and adverse reactions were compared between the two groups. Results: After treatment, blood glucose indicators in both groups showed significant improvement compared to pre-treatment levels (P<0.05). Compared to the metformin group, the combination group demonstrated superior reductions in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), and 2-hour postprandial blood glucose (2hPBG) (P<0.05). Both groups showed significant increases in fasting and 2-hour postprandial C-peptide levels compared to pre-treatment levels (P<0.05). Moreover, fasting and 2-hour postprandial C-peptide levels in the combination group were higher than those in the metformin group (P<0.05). HOMA-beta was higher and HOMA-IR was lower in the combination group than in the metformin group (P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusion: The combination of glipizide and metformin demonstrates a synergistic hypoglycemic effect in patients with newly diagnosed T2DM, and can effectively improve pancreatic beta-cell function with good safety.