Primary liver cancer is a major global health challenge, of which hepatocellular carcinoma is the most common. For patients with advanced liver cancer, sorafenib is a first-line targeted drug that occupies a dominant position in clinical applications. Sorafenib is a multi-kinase inhibitor commonly used in clinical practice, which can effectively inhibit tumor cell proliferation, promote cell apoptosis and inhibit angiogenesis. However, the emergence of drug resistance has hindered the development of treatment programs, which is an urgent problem to be solved. Recent studies have revealed many mechanisms and influencing factors of sorafenib resistance (such as epigenetic regulation, programmed cell death, metabolic reprogramming and tumor microenvironment changes). This review not only summarizes the above mechanisms, but also summarizes the combined application of sorafenib with other drugs (such as molecular targeted drugs, other anti-angiogenesis drugs, cytotoxic drugs, immunotherapy drugs, etc.). Finally, potential strategies and research directions to overcome drug resistance (such as targeting epigenetic pathways or metabolic reprogramming) are discussed to provide suggestions for future in-depth research and clinical applications.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.