Type II diabetes mellitus (T2DM) is a global epidemic affecting people of all ages in developed and developing countries. The disease is usually characterized by insulin resistance and glucose intolerance; therefore, oral antidiabetic drugs such as thiazolidinediones (TZDs) and biguanide metformin are used to counter these defects. Due to the varied action mechanisms of TZDs and Metformin, their effects on insulin sensitivity and glucose tolerance may differ. Therefore, the current study was carried out to compare the effects of Metformin and TZDs on insulin sensitivity and glucose tolerance among patients with T2DM.Two methods, including using a well-outlined search strategy in 5 electronic databases including ScienceDirect, Google Scholar, PubMed, Scopus, and Embase, and a manual search which involved going through the reference lists of studies from the electronic databases were used to retrieve studies published between 2000 and 2022. Additionally, data analysis of outcomes retrieved from the studies eligible for inclusion and the methodological quality was carried out using the Review Manager software (RevMan 5.4.1) and STATA.The meta-analysis has shown that TZDs have a significantly better overall effect on fasting plasma glucose (FPG) (SMD:0.61; 95% CI:0.06, 1.16: p = 0.03) and insulin sensitivity than Metformin (Mean QUICKI: 0.306 ± 0.019 vs. 0.316 ± 0.019, respectively; p=0.0003). However, the TZDs and Metformin offer the same effect on glycemic control as assessed using HBA1c levels (MD: 0.10; 95% CI: -0.20, 0.40; p = 0.52).TZDs offer better insulin sensitivity and glucose tolerance improvements compared to Metformin. This evidence contradicts the current guidelines by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE), which recommend the use of Metformin as the first-line drug monotherapy for patients with T2DM.