Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor <b>XD14</b> and well-established HDAC inhibitors. The most promising new hybrids, <b>49</b> and <b>61</b>, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. <b>49</b> induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, <b>61</b>, induced significantly more apoptosis than the related control compounds <b>62</b> (no BRD4(1) affinity) and <b>63</b> (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, <b>61</b> was well tolerated in an <i>in vivo</i> zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.