Diabetes is a major problem that has reached an alarming level, nearly half a billion people live with diabetes worldwide and estimated to increase to 51% by 2045. Diabetes mellitus is a complex chronic illness associated with a state of elevated levels of blood glucose or hyperglycemia. One of the therapeutic strategies to suppress postprandial hyperglycemia is namely inhibiting glucose absorption through inhibition of bio-catalysts involved in the digestion of carbohydrates such as α-amylase and α-glucosidase. In this paper, thirteen sulfonamide chalcones 3a-3m were synthesized using the Claisen–Schmidt condensation reaction by reacting sulfonyl aminoacetophenones with benzaldehydes and tested for their activity as α-glucosidase inhibitors. The results showed that the para position of secondary amine (3c) greatly influenced the inhibition results, likewise the effect of the electron-donating groups (3e). 3c provides very strong inhibitory activity with IC₅₀ 1.04 ± 0.19 μM. The finding proves that the sulfonamide chalcone has enormous potential as an α-glucosidase inhibitor and opens up opportunities to find new compounds that have better activity.