Abstract: As an important first-line drug for advanced hepatocellular carcinoma (HCC), lenvatinib shows non-inferior therapeutic effects to sorafenib as well as better performance in certain aspects. However, lenvatinib resistance emerged eventually as most other anticancer drugs. Epidermal growth factor receptor (EGFR) bypass activation, the overexpression of fibroblast growth factor receptor 1 (FGFR1) and the appearance of cancer stem cells in HCC are the causes of lenvatinib resistance. Lenvatinib combined with immune checkpoint inhibitors (ICIs) has been proven to have good efficacy in clinical trials. This review summarizes the new research findings on the mechanism of lenvatinib resistance and new strategies for improving the efficacy of lenvatinib in recent years, which could be helpful for treatment of HCC patients with lenvatinib.