Background/Objectives. Globally, hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and represents the third leading cause of cancer-related mortality. Despite advances in diagnosis and treatment, the overall prognosis of HCC remains poor, largely due to late-stage presentation and high rates of vascular invasion. Portal vein thrombosis constitutes a significant complication of HCC, with an occurrence rate of 35–50%. Portal vein tumour thrombosis (PVTT) represents an aggressive form that is closely linked to decreased patient survival. The incidence of PVTT increases over time, from approximately 21% in the first year after diagnosis to nearly 46% by the third year, highlighting its high prevalence and progressive nature. The introduction of immunotherapy has marked a paradigm shift in the management of HCC. Immune checkpoint inhibitors, particularly those targeting the PD-1/PD-L1 and CTLA-4 pathways, have demonstrated durable responses and significant survival benefits in certain patients with advanced HCC. Furthermore, emerging evidence suggests that combining immunotherapy with local or systemic therapies, such as trans arterial chemoembolization, hepatic arterial infusion chemotherapy, radiotherapy or tyrosine kinase inhibitors, may further enhance antitumor efficacy by modulating the tumour microenvironment and promoting synergistic immune activation. Method: This narrative review provides a comprehensive evaluation of immunotherapy in patients with HCC and PVTT, with a focus on its efficacy as both monotherapy and in combination with other treatment modalities in terms of tumour response, progression-free survival, and overall survival. It also addresses safety, patient selection, and emerging strategies to optimize outcomes in this high-risk population. Conclusions: The combination of multiple therapies could improve the patient’s prognosis by achieving objective response rate of almost 82%, disease control rate of 97% and progression free survival of 12.9 months with quadruple therapy (HAIC-TACE combined with targeted and immunotherapy).