Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, most often arising in the setting of chronic liver disease and cirrhosis. Although tyrosine kinase inhibitors have long represented the cornerstone of systemic therapy in advanced stages, therapeutic resistance and disease progression are frequent. Recent advances in immunotherapy, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway, have reshaped the therapeutic landscape of HCC. Pembrolizumab has demonstrated clinically meaningful antitumor activity and an acceptable safety profile in patients previously treated with sorafenib, as reported in pivotal clinical trials. This article highlights the therapeutic role of pembrolizumab as a second-line option in advanced HCC and discusses its place within current evidence-based treatment strategies, emphasizing the growing importance of immunotherapy in the multidisciplinary management of this disease.