Thiazolidinediones (TZDs) are a well-known class of antidiabetic agents predominantly recognized for their action as peroxisome proliferator-activated receptor gamma (PPAR-γ) modulators. Despite their role in improving insulin sensitivity, the clinical use of TZDs is limited by notable side effects like fluid retention, weight gain, liver toxicity, and an increased risk of heart failure. However, emerging evidence suggests their potential to affect multiple biochemical targets beyond PPAR-γ activation. This review focuses on the various antidiabetic mechanisms of TZDs, encompassing their involvement in inhibiting key targets such as α-glucosidase, α-amylase, aldose reductase, Protein tyrosine phosphatase 1 B (PTP1B), and Dipeptidyl peptidase-4 (DPP-4), as well as their emerging role as mitochondrial uncouplers. Understanding the mechanisms helps in designing newer agents that could improve the safety as well as ameliorate the off-target effects of existing thiazolidinediones. This review also offers a foundation for future drug development and therapeutic opportunities of TZDs in managing complex metabolic disorders like diabetes.