Gymnema sylvestre (GS) is a powerful antidiabetic plant that has been utilized in ayurvedic, folk and homeopathic medicine for centuries. In this research, we evaluated the antidiabetic potential of methanolic leaf extract of Gymnema sylvestre. Fractionation was carried out using column chromatography and a total of twenty-eight (28) sub-fractions were obtained which were further screened and pooled into three (3) fractions (A, B and C) by thin layer chromatography based on their retention factor (Rf) values. The fractions were subjected to in vitro α-amylase and α-glucosidase inhibition activity. Some of the compounds identified from LC-MS were subjected to in silico analysis between all the ligands and the receptors with the aid of a docking software. Ligands were imported for visual screening into PyRx software while Biovia Discovery Studio Visualizer was used for protein preparation. Analysis of the properties of drug likeliness of the ligands was done via SwissADME online server according to Lipinski’s Rule of Five. Final docking analysis was done through AutoDockVina and Biovia Discovery Studio client 2020. Fraction C showed the best IC50 of 0.84µg/ml α-glucosidase inhibitory activity when compared with fraction A and B, 2.00µg/ml and 1.58µg/ml (α-glucosidase), fraction A produced the best α-amylase activity among the fractions with IC50 of 16.78µg/ml, fraction B with 23.17µg/ml and fraction C with 28.22µg/ml. Molecular docking analysis of the ligands Orcinol (-5.5 kcal/mol) showed strong binding interaction with α-amylase, followed by 3-hydroxy-3'-methoxyflavone and Curcumin (-7.1 kcal/mol and -7.6 kcal/mol respectively) compared to acarbose (-8.0 kcal/mol) and Glyinflanin A (-8.4 kcal/mol) interactions. The binding affinity of Orcinol, 3-hydroxy-3'-methoxyflavone, Curcumin and Glyinflanin A (-5.7 kcal/mol, -8.0 kcal/mol, -7.6 kcal/mol and -9.1 kcal/mol respectively) were lower compared to acarbose (-9.7 kcal/mol) interaction with α-glucosidase. Thus, compounds identified from Gymnema sylvestre were found to have antidiabetic potentials with Orcinol displaying the most effective binding affinity in potential for drug development.