•Novel 5-styryl-2-(4-tolylsulfonamido)chalcones were synthesized and characterized•The geometry of a representative example was established using X-ray crystallography•The experimental data was complemented with density functional theory•The compounds were evaluated in vitro against α-glucosidase and α-amylase, and for antioxidant properties•Their mechanism of antioxidant effect was evaluated at theoretical level Sulfonylation of the 5-styryl-2-aminochalcones with p-toluenesulfonyl chloride in pyridine afforded novel 5-styryl-2-sulfonamidochalcone hybrids. XRD analysis of a representative compound helped to confirm the presence of a six-membered N–H···O intramolecularly hydrogen bonded chair-like pseudo ring. Topology was determined through Hirshfeld surface analysis and the energy of frontier molecular orbitals was used to evaluate the stability of this compound. The inhibitory effect of the test compounds against α-glucosidase and α-amylase activities was evaluated in vitro through enzymatic assays, and their antioxidant properties also in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) radical scavenging assays. An in vitro cell-based antioxidant activity assay of the most active compounds, 2f and 2h, involving lipopolysaccharide (LPS) induced reactive oxygen species (ROS) production also confirmed their capability to scavenge free radicals. Molecular modelling was used to postulate ligand–enzyme interactions and to rationalize the mechanism of antioxidant effect of these compounds. Display omitted