AIM: This study compared the effects of hypoglycaemic drugs on beta-cell function among type 2 diabetes mellitus (T2DM) patients through a network meta-analysis of randomized controlled trials (RCTs). METHODS: We searched the PubMed, EMBASE, and Cochrane Library databases for RCTs of different hypoglycaemic drugs as T2DM treatment from database inception to December 1, 2024. The primary outcome was homeostasis model assessment-β (HOMA-β), and the secondary outcome was glycated haemoglobin (HbA1c). Direct and indirect evidence types were combined to calculate weighted mean difference (WMD) and 95% confidence interval (CI) values for the change in (△) HOMA-β and △HbA1c, and to determine surface under the cumulative ranking curve (SUCRA) values. RESULTS: A total of 58 RCTs involving 16,345 T2DM patients were incorporated into this network meta-analysis. The mean patient age was 66.70 years, and 54.14% were male. For improving HOMA-β, the top treatments were glimepiride + rosiglitazone (WMD = 81.83, 95% CI 45.85-117.82) and glibenclamide + rosiglitazone (WMD = 79.51, 95% CI 40.66-118.36). Acarbose (WMD = 60.90, 95% CI 27.56-94.25) ranked third as monotherapy. For reducing HbA1c, glibenclamide + rosiglitazone was the most efficacious treatment (WMD = - 2.48, 95% CI - 3.67 to - 1.29), followed by metformin + exenatide (WMD = - 1.77, 95% CI - 2.25 to - 1.29) and liraglutide (WMD = - 1.77, 95% CI - 2.33 to - 1.21). The treatment with the highest SUCRA value for HOMA-β improvement was glimepiride + rosiglitazone (95.1%), followed by glibenclamide + rosiglitazone (94.9%). For HbA1c improvement, glibenclamide + rosiglitazone had the highest SUCRA value (97.6%). CONCLUSIONS: The combination of glimepiride/glibenclamide and rosiglitazone was the most effective hypoglycaemic regimen for protecting beta-cell function and improving glycaemic control in T2DM treatment, possibly due to control of HbA1c and glycotoxicity.