Natural products are the emerging compounds for treating a wide variety of ailments. In a recent trend, rational semi-synthesis remained an impressive approach for developing inhibitors with pronounced activity. 3′,4′-methylenedioxy have been found to be present in a variety of compounds expressing anti-mycobacterial, anti-inflammatory, anti-cancer, analgesic, anti-pyretic, etc. The present study focuses on the rational development of ( E )-3-(benzo[d][1,3]dioxol-5-yl)-1-(1-methoxy-9 H -carbazol-3-yl)prop-2-en-1-one from murrayanine and 3′,4′-(methylenedioxy)acetophenone and investigating the anti-inflammatory activity of the fabricated hybrid. The influence of the 3′,4′-methylenedioxy group present in the ring-B of the murrayanine-chalcone scaffold was explored. The optimization of the essential structure and their emphasis on pronounce activity was determined. The present work revealed the fabrication of 3′,4′-methylenedioxy moiety containing murrayanine based chalcone through a semi-synthetic approach. The compound through 3′,4′-methylenedioxy portion exhibited anti-inflammatory potential after 3 hrs by inhibiting cyclooxygenase-2 (COX-2) and lipoxygenase (LOX), the major intermediates and promoter of inflammatory responses. Lipophilicity may be considered as a key factor in exhibiting the biological activity via swiftly crossing the biological membrane. The research has opened new doors for developing the natural product based inhibitors which will have better edema reducing potentials with low toxicity. The study will inspire the chemists in developing therapeutically active natural products based 3′,4′-methylenedioxy compounds.