EZH2 inhibitors that prevent trimethylation of histone lysine 27 (H3K27) are often limited to the treatment of a subset of hematological malignancies. In most solid tumors, EZH2 inhibitors induce reciprocal H3K27 acetylation that subsequently results in acquired drug resistance. The combination of EZH2 and BRD4 inhibitors to resensitize solid cancer cells to EZH2 inhibitors has proven to be effective, underlying the significance of developing dual inhibitors. Herein, we present the design, synthesis, and biological evaluation of first-in-class dual EZH2/BRD4 inhibitors. Our most promising compound, YM458, displays potent inhibitory activity against EZH2 and BRD4 and remarkable antiproliferative capacity against 11 solid cancer cell lines. Its in vivo therapeutic potential is validated in both lung cancer and pancreatic cancer xenograft tumor mice models, highlighting the potential of EZH2/BRD4 dual inhibitors to target a broad scope of EZH2 inhibitor-resistant solid tumors.