Histone deacetylases have proven to be promising targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of 20 novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core structure. Five newly obtained compounds displayed excellent HDAC6 inhibitory activities. Among them, compounds WY-12 and WY-15 also exhibited excellent antiproliferative activities against six human tumor cell lines. WY-15 could increase the level of acetylated histone H3 in a dose-dependent manner. Furthermore, WY-15 remarkably induced cell cycle arrest of Sy5y cancer cells in G /G phase. Finally, the high potency of compound WY-15 toward HDAC6 was rationalized by molecular docking study.