The Aldose Reductase (AR) catalyses the conversion of glucose to sorbitol, which is a major cause of diabetes related complications. Therefore, AR inhibition has emerged as a key strategy for preventing and reducing long-term diabetic complications. Natural products are the main source of lead molecules in drug discovery. In particular, polyphenolic compounds such as flavonoids are extensively studied for antidiabetic activity. A molecular data set of twenty-five naturally occurring AR inhibitors belonging to flavone, isoflavone, flavonol, and dihydroflavone were selected for in-silco analysis. All selected molecules have a common benzopyran-4-one core structure decorated with hydroxyl and methoxy function at various positions. The structure-activity relationship (SAR) was established for AR inhibition with structural or molecular finger prints. The SAR suggests that 3-phenyl substitution in benzopyran-4-one is detrimental to AR inhibition while 2-phenyl substitution is more effective. The presence of 3-OH did not decrease the AR inhibition to a greater extent, which suggests that flavonols are potential leads. Furthermore, molecular docking studies were carried out in order to gain a better understanding of the AR inhibitory potency of these molecules at a biomolecular level and to propose a binding mode that explains the aforementioned SARs. Docking experiments revealed that the aromatic ring contributed to π−π interaction with the Trp111 residue. In addition, the molecule forms hydrogen bonds with His110, which could result in strong AR inhibition. Overall, our computational analysis suggested that the 2-phenyl benzopyran-4-one core could be a potential AR inhibition lead for further drug development.