Diabetes is a chronic metabolic disorder characterized by persistently high blood glucose levels due to insulin malfunction, defective insulin secretion, or both. Chromen-4-one, known to have diverse biological activity, is a core structure found in many natural products, particularly in the flavonoid and isoflavonoid families. The study aims to explore the potential of Chrome-4-one derivatives as a potential antidiabetic agent through the α-glucosidase inhibition mechanism. The compounds were retrieved from the PubChem database, optimized, and prepared using ChemDraw 12.0, Spartan14, and UCSF Chimera. The post-docking analysis was done using BIOVIA Discovery Studio. Theoretical oral bioavailability and toxicity predictions were performed using ADMETlab3.0. Molecular docking of the compounds against the α-glucosidase enzyme (PDB ID: 3A4A) was carried out using AutoDock Vina. According to Lipinski’s rule of five (5), all the ligands passed the oral bioavailability and are druggable. The binding score of all the ligands was better than the native ligand (-5.7 Kcal/mol) but slightly lower than that of Acarbose (-9.0 Kcal/mol), except for L7 (Myricetin), which equals the standard drug. The ligands revealed good interaction with the enzyme’s active site residues. The most notable interactions were hydrogen bonding, van der Waals, pi-anion, pi-cation, pi-pi T-shape, pi-sigma, and carbon-hydrogen bond. The ligands interacted with the key catalytic residues; ASP352, GLU277, GLU411, TRY158, and ARG442, responsible for α-glucosidase inhibition. The result of the study suggests that the chromen-4-one derivatives have the potential to be utilized as a lead molecule for orally available α-glucosidase inhibitors.