This study delves into the exploration of bioactive constituents derived from Salvia officinalis and Glycyrrhiza glabra, with a focus on their potential to modulate peroxisome proliferator-activated receptor gamma (PPARG), a crucial regulator of glucose homeostasis and a key target for diabetes management. Through the rigorous application of in silico methodologies, the interactions between PPARG and six natural compounds, including kanzonol X, glabrol, linolenic acid, glycyrrhizin, carnosic acid, and licoflavone A, were meticulously examined. Molecular docking studies unveiled a notable binding affinity between kanzonol X and glabrol to the PPARG receptor, indicating their potential effectiveness in regulating blood glucose levels through PPARG activation. Molecular dynamics simulations affirmed the stability of the PPARG-ligand complexes, highlighting the significance of hydrogen bonds in maintaining their stability. Furthermore, computational techniques were utilized to assess the absorption, distribution, metabolism, and excretion (ADME) properties as well as the compounds’ cardiotoxicity. Encouragingly, these natural substances exhibited efficient cellular uptake, favorable bioavailability, and demonstrated no cardiotoxic effects. Kanzonol X and glabrol, abundant in G. glabra, have emerged as strong candidates for regulating blood glucose levels regulation through PPARG activation. Although computational methodologies have offered vital insights, unlocking the full potential of these compounds necessitates rigorous research and clinical trials to validate the effectiveness and safety of kanzonol X and glabrol in managing diabetes for this patient population.