Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound <b>20</b> exhibited excellent inhibitory activity against HDAC1 (IC<sub>50</sub> = 0.12 μM) and EZH2 (IC<sub>50</sub> = 0.059 μM), it also showed good antiproliferation activity against MV4-11 (IC<sub>50</sub> = 0.17 μM), which has more potential than the cocktail therapy of SAHA and GSK126 (IC<sub>50</sub> = 0.40 μM). <b>20</b> suppressed tumor growth in vivo, which was as good as the combination therapy. These results suggested that <b>20</b> may be a promising drug candidate for treating hematological malignancies.