A series of five chalcone derivatives were synthesized by Claisen–Schmidt condensation of acetophenone with appropriately substituted benzaldehyde in the presence of aqueous alkali. The synthesized compounds were characterized by their IR, NMR, and Mass spectral data. These compounds have been subjected to anti-inflammatory screening using the carrageenan-induced rat hind paw edema model. Chalcone derivatives at dose 25 mg/kg by oral route inhibited significantly the formation of edema. Chalcone posses a highly electrophilic a,b-unsaturated carbonyl moiety showed better anti-inflammatory activity.