AbstractType 2 diabetes is common and involves α‐glucosidase inhibition to regulate glucose. We synthesized twenty E‐arylidene steroids with hydroxy and methoxy groups on the aromatic ring. Compounds 3 a, 5 a, 5 b, and 5 d showed notable inhibition, with IC₅₀ values ranging from 1.84±0.28 to 9.25±2.53 μM. Key features for bioactivity include ortho methoxy and α‐hydroxy. Various inhibition mechanisms were observed. In silico studies elucidate the possible binding modes of E‐arylidene steroids, confirming their enzymatic mechanisms of non/un‐competitive inhibitors. Allosteric site 2 emerges as a potential binding site for compounds 3 a, 5 a, and 5 b. Compound 5 d holds promise as a potent α‐glucosidase inhibitor compared to acarbose at the orthosteric receptor binding site.