Abstract <p><b>Objective:</b> This study aimed to design, synthesize, and evaluate thiazolidinedione and rhodanine-based quinazoline derivatives (<b>Va–Vc</b>) as dual inhibitors of α-amylase and α-glucosidase, with an investigation into their pharmacokinetic properties and mechanism of action using a computational approach. <b>Methods:</b> The compounds were designed computationally and synthesized using appropriate synthons. <i>In silico</i> molecular docking and molecular dynamics simulations were employed to explore their interactions with α-amylase, GLUT-4, and homology-modeled α-glucosidase. Pharmacokinetic properties, including drug-likeness, ADME, and toxicity, were predicted. Network pharmacology and experimental validation were used to assess the modulation of PI3K-AKT, MAPK, and EGFR signaling pathways, as well as inhibitory activities against α-amylase, α-glucosidase, and glucose uptake by yeast cells. <b>Results and Discussion:</b> The derivatives exhibited promising inhibitory activities. Substituted benzylidine thiazolidine-2,4-dione showed IC₅₀ values of 22.59 ± 0.30 µM for α-amylase and 43.50 ± 1.23 µM for α-glucosidase, with 58.23 ± 0.14% glucose uptake. Substituted benzylidene-4-oxo-2-thioxothiazolidin-3-yl acetic acid displayed IC₅₀ values of 13.48 ± 1.38 µM for α-amylase and 65.94 ± 0.14 µM for α-glucosidase, with 57.23 ± 0.13% glucose uptake. These compounds modulated key signaling pathways, contributing to their inhibitory effects and favorable pharmacokinetic profiles. <b>Conclusions:</b> The study highlights the potential of thiazolidinedione and rhodanine-based quinazoline derivatives as novel α-amylase and α-glucosidase inhibitors, offering promising therapeutic potential for managing diabetes mellitus. </p>