Primary liver cancer is a highly prevalent malignant tumor worldwide, with hepatocellular carcinoma (HCC) being characterized by insidious onset and rapid progression. Most patients are diagnosed at advanced stages, losing the opportunity for radical surgery, making systemic therapy the core approach to prolong survival and improve quality of life. Historically, molecular targeted therapy has been the mainstay of systemic treatment for advanced liver cancer, offering some control over tumor progression but with limitations such as low objective response rates, frequent drug resistance, and limited survival benefits. The advent of immune checkpoint inhibitors has revolutionized the landscape of systemic liver cancer therapy, providing hope for long-term survival in advanced patients through their unique mechanism of reshaping the tumor immune microenvironment and activating endogenous anti-tumor immunity. However, monotherapy with immune checkpoint inhibitors is effective only in a minority of immunologically favorable patients, limiting overall benefit. In recent years, the combination of targeted therapy and immunotherapy (targeted-immunotherapy combination) has broken through the efficacy bottleneck of monotherapy through synergistic anti-tumor effects, becoming the standard first-line treatment for advanced liver cancer. This article provides a comprehensive review of the mechanisms of action, core clinical research progress, and optimization strategies for clinical translation of targeted-immunotherapy combination therapy in liver cancer, aiming to provide references for clinical practice and future research in this field.