Liver cancer is one of the most common and devastating causes of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers and represents a significant global health issue. There is currently no effective systemic treatment for patients with advanced liver cancer. One study suggests that sorafenib may be effective against hepatocellular carcinoma. Sorafenib can significantly extend the median survival time of patients, but only by 3–5 months. Furthermore, it is linked to severe adverse side effects and frequently leads to drug resistance. In this review, we offer a critical analysis of the factors contributing to sorafenib resistance in HCC.