A series of novel histone deacetylase inhibitors (HDACIs)/chalcone hybrids bearing hydroxamic acid or 2- aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structural formula of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds showed moderate to strong Histone deacetylase (HDAC) inhibitory activity. In particular, compounds 3b, 3c, 3d and 3e exhibited the highest Histone deacetylase inhibitory activity compared to suberoylanilide hydroxamic acid (SAHA) as reference drug. The results indicated that these HDACIs/chalcone hybrids could serve as a promising lead compounds for further optimization as antitumor agents