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 20 exhibited excellent inhibitory activity against HDAC1 (IC50 = 0.12 μM) and EZH2 (IC50 = 0.059 μM), it also showed good antiproliferation activity against MV4-11 (IC50 = 0.17 μM), which has more potential than the cocktail therapy of SAHA and GSK126 (IC50 = 0.40 μM). 20 suppressed tumor growth in vivo, which was as good as the combination therapy. These results suggested that 20 may be a promising drug candidate for treating hematological malignancies.