Hepatocellular carcinoma (HCC) is characterized by marked biological heterogeneity, and patients with intermediate- or advanced-stage disease often present with high tumor burden, portal vein tumor thrombus, or extrahepatic progression, making it difficult for a single local or systemic treatment modality to achieve adequate intrahepatic tumor control while addressing systemic disease. Yttrium-90 selective internal radiation therapy (⁹⁰Y-SIRT) selectively delivers radioactive microspheres through the hepatic artery and is characterized by precise local irradiation, limited embolic effects, and the potential for personalized dosimetry. It has therefore become an important transarterial treatment modality for HCC. This review summarizes the therapeutic principles and dosimetric basis of ⁹⁰Y-SIRT and focuses on its clinical application in intermediate- and advanced-stage HCC, including comparisons with transarterial chemoembolization (TACE), its use in advanced HCC and patients with portal vein tumor thrombus, and its sequential or combined use with targeted therapy, immunotherapy, and targeted therapy plus immunotherapy. The evidence for combination or sequential treatment with TACE, as well as conversion hepatectomy, downstaging before liver transplantation, and bridging therapy after ⁹⁰Y-SIRT, is also reviewed. Current evidence suggests that ⁹⁰Y-SIRT can provide durable intrahepatic tumor control in selected patients with predominantly liver-limited disease and preserved liver function and may create opportunities for subsequent systemic or potentially curative treatment. Personalized dosimetry and higher absorbed tumor doses appear to be associated with tumor response and survival outcomes. However, evidence supporting combinations with systemic or immune therapies remains largely derived from retrospective studies and small, single-arm prospective trials, and the optimal patient selection, dosimetric strategy, treatment sequence, and long-term benefits remain uncertain. Future prospective multicenter randomized studies should focus on patient selection and personalized dosimetry, clarify optimal combinations and treatment sequences with systemic therapy, and establish comprehensive endpoints incorporating tumor control, hepatic function, conversion to curative treatment, and quality of life, thereby facilitating the standardized application of ⁹⁰Y-SIRT in the multidisciplinary management of intermediate- and advanced-stage HCC.