A series of novel fluoro-substituted chalcone derivatives have been synthesized. All synthesized compounds were characterized by H-1 nuclear magnetic resonance (NMR), C-13 NMR, and elemental analysis. Their anti-proliferative activities were evaluated against five cancer cells lines, namely, A549, A498, HeLa, A375, and HepG2 using the MTT method. Most of the compounds showed moderate to high activity with IC50 values in the range of 0.029-0.729 mu M. Of all the synthesized compounds, 10 and 19 exhibited the most potent anti-proliferative activities against cancer cells, and 10 was identified as the most promising compound. (C) 2016 Elsevier Ltd. All rights reserved.