In this study, thirty-eight chalcone analogs were synthesized and evaluated for nitric oxide (NO) inhibition activity on RAW 264.7 cells. Among these compounds, chalcones bearing furanyl group showed remarkable anti-inflammatory activity. Both compounds 2d and 2j were identified as the most potent NO inhibitor on IFN-c/LPS-activated RAW 264.7 cells. In order to examine the structure–activity relationship, a 3D QSAR analysis was carried out by comparative molecular field analysis (CoMFA) method on the selected chalcones. Partial least square analysis produced a statistically coherent model with good predictive value, r 2 = 0.989 and a good cross validated value, q2 = 0.583.