Lenvatinib is a multi-target tyrosine kinase inhibitor widely used in the treatment of hepatocellular carcinoma (HCC). Its primary mechanism of action involves inhibiting signal pathways such as vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR), thereby reducing tumor cell proliferation and angiogenesis and affecting the tumor's immune microenvironment. In the treatment of liver cancer, although lenvatinib monotherapy has shown good clinical effect, the problem of drug resistance is becoming more and more serious. This resistance may be caused by a variety of factors, including genetic mutations, signaling pathway remodeling, and changes in the tumor microenvironment. In order to overcome drug resistance, the combination of lenvatinib and other therapeutic strategies has gradually become a research hotspot, and it is worth noting that the combination of lenvatinib and immune checkpoint inhibitors (ICIs) has shown a good application prospect. This combination not only enhances the anti-tumor immune response but also helps improve therapeutic efficacy. However, combination therapy also faces challenges regarding safety and tolerability. Therefore, studying the mechanisms of resistance and identifying relevant biomarkers is particularly important, as it aids in early diagnosis and personalized treatment. This article reviews the mechanisms of lenvatinib in treating liver cancer, the mechanisms and efficacy of its combination with immune checkpoint inhibitors, the causes of resistance, the exploration of biomarkers, and other novel combination therapy strategies for lenvatinib. We hope to provide insights into the use and research of lenvatinib in clinical and scientific settings, offering new strategies for the treatment of liver cancer.