AbstractLenvatinib is a clinically effective multikinase inhibitor approved for first‐line therapy of advanced hepatocellular carcinoma (HCC). Although resistance against lenvatinib often emerges and limits its antitumor activity, the underlying molecular mechanisms involved in endogenous and acquired resistance remain elusive. In this study, we identified focal adhesion kinase (FAK) as a critical contributor to lenvatinib resistance in HCC. The elevated expression and phosphorylation of FAK were observed in both acquired and endogenous lenvatinib‐resistant (LR) HCC cells. Furthermore, inhibition of FAK reversed lenvatinib resistance in vitro and in vivo. Mechanistically, FAK promoted lenvatinib resistance through regulating lysine‐deficient kinase 1 (WNK1). Phosphorylation of WNK1 was significantly increased in LR‐HCC cells. Further, WNK1 inhibitor WNK463 resensitized either established or endogenous LR‐HCC cells to lenvatinib treatment. In addition, overexpression of WNK1 desensitized parental HCC cells to lenvatinib treatment. Conclusively, our results establish a crucial role and novel mechanism of FAK in lenvatinib resistance and suggest that targeting the FAK/WNK1 axis is a promising therapeutic strategy in HCC patients showing lenvatinib resistance.