Computer-aided drug design and structure-based drug design techniques were used to find 18 novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors. At 1 μM and 0.05 μM, the majority of the target compounds inhibited BTK and FLT3 by more than 80%, respectively. Among these, compound RSH-7 inhibited BTK and FLT3 most effectively, with IC50 values of 47 and 12 nM, respectively, which were superior to spebrutinib (BTK IC50 = 54 nM) and sorafenib (FLT3 IC50 = 33 nM). RSH-7 effectively inhibited the proliferation of multiple hematological malignancy cells with IC50 values ranging from 3 to 17 nM, which were 81–133 folds lower than spebrutinib. Furthermore, RSH-7 strongly inhibited BTK and FLT3 signaling and induced apoptosis in jeko-1 cells by upregulating pro-apoptotic proteins and downregulating Bcl-2 levels. RSH-7 showed moderate in vitro ADME properties. Importantly, RSH-7 demonstrated highly efficacious and well-tolerated in jeko-1 (50 mg/kg, TGI = 79.78%) and MV4-11 (20 mg/kg, TGI = 94.84%) xenograft models. These findings indicated that RSH-7 may be a promising lead compound for the treatment of hematological malignancies.