Objective: Objective of this study is to evaluate the pyruvate dehydrogenase kinase 3 (PDK3) inhibitory potential of certain polyphenolic compounds including, ellagic acid, quercetin, limonin, simvastatin, citral, capsaicin, vanillin, dl-α-tocopherol acetate and ursolic acid. Compounds showing best inhibition was further evaluated for their therapeutic potential. Methods: Molecular docking was performed to evaluate the interactions between these selected polyphenols with PDK3. Ellagic acid and quercetin were binding to the PDK3 most efficiently, as observed with docking and fluorescence studies. Isothermal titration calorimetry further confirmed the significant binding of ellagic acid and quercetin with PDK3. Furthermore, molecular dynamics simulations studies were performed to check the dynamics of ellagic acid/quercetin-PDK3 complex and interatomic motions were calculated. Cytotoxicity and antiproliferative properties of ellagic acid and quercetin was quantitated by MTT assay. Results: Ellagic acid and quercetin significantly binds and inhibits the kinase activity of PDK3. Conformational dynamics of ligand-PDK3 complex during molecular dynamics simulation revealed the formation of a stable complex which was maintained by significant number of hydrogen bonds throughout the 100 ns trajectories. Fluorescence experiments showed that ellagic acid, quercetin and limonin along with DL-α-tocopherol exhibits significant fluorescence quenching. Both ellagic acid and quercetin showed a superior anti-proliferative and minimal cytotoxic activity towards the cancer (A549 and HepG2) and normal cells (HEK293), respectively. Conclusion: Ellagic acid and quercetin can be used for its modulatory effects on metabolic reprogramming and its scaffold could be exploited for the development of lead molecule against PDK3 associated diseases. Our findings confirm that all selected polyphenolic compounds interact to the PDK3 with distinct binding efficiency and thus could be further evaluated for therapeutic uses after a certain validation. Both ellagic acid and quercetin inhibit PDK3 and can be further exploited as a scaffold lead to design potent and selective molecules against PDK3 to ameliorate diabetes and metabolic syndromes.