Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial nuclear receptor in humans, playing a central role in regulating glucose homeostasis and lipid metabolism. Its activation holds significant potential not only for managing Type 2 diabetes but also for preventing its onset by addressing insulin resistance, a key precursor to the disease. This study explores the potential of polyphenols as natural modulators of PPARγ, aiming to enhance strategies for preventing the progression of insulin resistance to Type 2 diabetes. Polyphenols, plant-derived bioactive compounds, possess strong bioactivity in modulating various cellular pathways, including those linked to PPARγ activation. Since insulin resistance can develop years before the onset of Type 2 diabetes, identifying compounds that enhance insulin sensitivity early is critical for disease prevention. Molecular docking studies were conducted on a library of 12,000 polyphenols to identify compounds with the strongest binding affinities for PPARγ. Among the candidates, Resveratrol and Epigallocatechin gallate (EGCG) emerged as top ligands, with docking scores of -9.38 kcal/mol and -8.77 kcal/mol, respectively, along with lower RMSD values (0.55 and 0.72). These compounds demonstrated strong binding to key receptor sites of PPARγ, potentially enhancing its activity and improving insulin sensitivity, thereby reducing the risk of Type 2 diabetes development. Moreover, the activation of the adiponectin signaling pathway was identified as a crucial mechanism underlying the beneficial effects of PPARγ in mitigating insulin resistance. Molecular dynamics simulations (MDSs) further validated the stability and efficacy of polyphenol–PPARγ complexes, confirming their sustained interactions and enhanced receptor activation. The pharmacokinetic profiles of these polyphenols revealed highly favorable characteristics, such as excellent bioavailability and non-toxicity, reinforcing their potential as preventive agents. Collectively, this study provides new insights into the modulation of PPARγ by polyphenols, offering a promising approach for delaying or preventing Type 2 diabetes through natural compounds that target early metabolic dysfunction.