A new series of thirty‐two fluorinated and/or hydroxylated 2‐arylidene‐1‐indanone derivatives were systematically designed, synthesized, and evaluated for their inhibitory activity against LPS‐stimulated ROS production in RAW 264.7 macrophages. 5/6‐Fluoro‐1‐indanone or 4‐, 5‐, 6‐, or 7‐hydroxyindanone moiety along with ortho‐, meta‐, or para‐hydroxyphenyl, furanyl or thiophenyl moiety was prepared and evaluated. Among the synthesized compounds, compound 11 possessing 6‐hydroxy‐1‐indanone moiety along with 5‐chlorothiophenyl moiety was found to have the most potent inhibitory effect on the production of ROS in LPS‐stimulated RAW 264.7 macrophages with an IC50 value of 3.29 μM.