Background: Glibenclamide remains widely used for glycemic control in type 2 diabetes mellitus (T2DM), but its comparative metabolic effects across glycemic, lipid, anthropometric, and cardiometabolic outcomes remain uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing glibenclamide with other antidiabetic therapies. Methods: We restricted eligibility to randomized trials in adults with T2DM. We performed random-effects meta-analyses for continuous outcomes; we assessed statistical heterogeneity using I², risk of bias using Cochrane RoB 2, and certainty of evidence using GRADE. Results: We retained 19 reports representing 18 unique randomized trials for the qualitative synthesis; after final verification of study design and population, 14 reports, each from a distinct trial, contributed data to at least one quantitative meta-analysis. RoB 2 was assessed for a principal eligible result from all 19 included reports (18 unique trials): 11 report-level results (57.9%) were at high overall risk of bias, and eight (42.1%) raised some concerns. Within the 14-report quantitative subset, 10 were at high overall risk of bias, and four raised some concerns. No significant difference was observed for HbA1c (MD −0.45%; 95% CI −1.05 to 0.16; I² = 99%) or fasting plasma glucose (MD −1.52 mmol/L; 95% CI −3.27 to 0.23; I² = 99%). Body weight was higher with glibenclamide (MD 2.41 kg; 95% CI 1.63 to 3.20; I² = 91%), and triglycerides showed a small nominal increase (MD 1.11 mg/dL; 95% CI 0.02 to 2.19; I² = 91%); both findings were supported by very low-certainty evidence and were not uniformly stable in leave-one-out analyses. Conclusions: Across randomized T2DM trials, the available evidence does not demonstrate consistent differences in most metabolic outcomes between glibenclamide and heterogeneous comparator therapies. Interpretation is limited by substantial clinical and statistical heterogeneity, high risk of bias, imprecision, and predominantly low or very low certainty of evidence. The pooled estimates should not be interpreted as evidence of therapeutic equivalence between drug classes, and comparative safety remains uncertain because hypoglycemia was reported inconsistently.