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In this study, potent coumarin derivatives containing oxime ester 1 ∼ 28 as α-glucosidase inhibitors were developed through a stepwise structure optimization, and the structure activity relationship was uncovered. Among them, compound 20 exhibited outstanding α-glucosidase inhibitory activity with IC50 of 2.54 ± 0.04 μM compared to 640.57 ± 1.13 μM of Acarbose. Kinetic study ascertained that compound 20 was a reversible and uncompetitive α-glucosidase inhibitor. 3D fluorescence results showed that the interaction of compound 20 with α-glucosidase caused the changes of microenvironments and polypeptide backbone structure of α-glucosidase. CD spectra results revealed that compound 20 decreased the α-helix content and increased the β-sheet content. Molecular docking analysis indicated that compound 20 well located into the active site and mainly bind with Phe157, His239, His279, Tyr71, and Arg312 to reduce the catalytic activity of α-glucosidase.