Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, and it is also one of the leading causes of tumor-related death worldwide. Due to hidden early symptoms, most patients are diagnosed in the intermediate-advanced HCC upon admission. For them, surgical resection, local ablation and liver transplantation are potential therapeutic options, whereas most patients have lost the opportunity of surgery. Along with recent in-depth exploration of the molecular mechanism of HCC and successful development of multiple targeted drugs, systemic therapy has become increasingly prominent in the treatment of HCC. Among them, targeted therapy combined with immunotherapy showcases significant therapeutic advantages. At present, multiple regimens of targeted therapy combined with immunotherapy have completed phase Ⅲ clinical trials and verified their efficacy and safety, which have been widely applied in clinical practice. Therefore, the combination of targeted therapy and immunotherapy will applied more through the whole process of treatment for intermediate-advanced HCC, which is expected to significantly improve the survival and prognosis of patients. In this article, the latest research progress in the field of first-line treatment for intermediate-advanced HCC was reviewed, providing theoretical basis and clinical guidance for targeted therapy combined with immunotherapy for HCC.