In the continuous effort to develop more potent and safe non-steroidal anti-inflammatory drug (NSAID), semi-synthetic halogen-containing murrayanine based chalcone was developed from murrayanine (1) and 1-(2,4-dichloro-5-fluorophenyl)ethanone (2) and screened for in vivo anti-inflammatory screening was performed in Swiss albino rats by employing the carrageenan-induced paw edema method. The in vivo anti-inflammatory activity chalcone compound (3) was found to be moderate as compared with the standard drug indomethacin in the carrageenan-induced paw edema method. The prop-2-ene-1-one compound demonstrated % edema reduction of 21.28%, 32.43%, and 45.77%, respectively over the 3 hrs duration. The compound may be believed to inhibit the inflammatory mediators like cyclooxygenase-1/2 (COX-1/2) and lipoxygenase (LOX) through the electron-withdrawing substituents present. Although, no structure-activityrelationships (SARs) cannot be predicted from this study and need further studies. The current study will draw the attention of global (medicinal)-chemists towards the rational development of semi-synthetic NSAID compounds with pronounced edema reducing activity.