Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target for the treatment of hepatocellular carcinoma (HCC) with aberrant FGFR4 signaling because of its important role in HCC progression and development. Several FGFR4 inhibitors are under clinical development. Using a 7-azaindole scaffold, we discovered a series of novel selective and covalent FGFR4 inhibitors by performing a structure-based design approach. Representative compounds 24 and 30 exhibited potent FGFR4 inhibition and high selectivity among kinases. Western blot analysis showed that compounds 24 and 30 significantly inhibited the FGF19/FGFR4 signaling pathway in HuH-7 cells and effectively suppressed the proliferation of HuH-7 HCC cells and MDA-MB-453 breast cancer cells. Moreover, compound 30 exhibited significant in vivo antitumor activity in a mouse HuH-7 xenograft model. Thus, compound 30 and the 7-azaindole scaffold can be applied to develop anticancer agents for the treatment of cancers characterized by aberrant FGFR4 signaling.