Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.