The field of treatment for advanced hepatocellular carcinoma (HCC) is witnessing a cutting-edge exploration aimed at surpassing traditional boundaries and leading medicine towards more precise and personalized directions. The introduction of molecular targeted therapy has injected new vitality into this field, revolutionizing treatment strategies by acting on specific sites of tumor cells, successfully improving patients' quality of life. Amidst this wave of transformation, hepatic arterial infusion chemotherapy (HAIC) has gained significant attention as an important local treatment approach. Its combined application with targeted drugs is expected to achieve synergistic effects, bringing more significant therapeutic outcomes for patients with advanced HCC. HAIC combined with sorafenib has shown significant potential in improving survival rates for patients with advanced HCC, particularly for those with portal vein invasion. However, the accompanying adverse events are challenges that cannot be ignored. Similarly, HAIC combined with lenvatinib has also shown good survival benefits and tolerability of adverse reactions in the treatment of advanced HCC, but related clinical studies are still insufficient. Overall, the clinical efficacy and safety of HAIC combined with targeted drug therapy require more high-quality evidence to support. Meanwhile, the rise of immunotherapy has become one of the focal points in the current treatment field, offering new hope for the treatment of advanced HCC by overcoming tumor immune tolerance through activating the body's immune response. HAIC combined with immune inhibitors has demonstrated superior efficacy in the treatment of advanced HCC and holds a significant position in HCC conversion therapy. Moreover, HAIC combined with targeted therapy not only shows remarkable advantages in tumor reduction and surgical conversion rates but is also unanimously recommended by domestic experts as an important treatment method for HCC patients with portal vein tumor thrombus. Despite this, HAIC combined therapy still faces a series of challenges, including how to select the dominant population, grasp the timing of treatment, determine the best treatment plan, and manage adverse reactions, which still need further exploration. Therefore, this paper aims to elaborate on the research progress of HAIC combined with systemic drugs for intermediate to advanced HCC, in order to provide useful references for the optimization of treatment plans.