According to the current international authoritative guidelines for hepatocellular carcinoma (HCC), the approved first-line therapy drugs include atezolizumab plus bevacizumab, sorafenib, and lenvatinib, while there are more options for second-line molecular targeted drugs, including regorafenib, cabozantinib, and ramucirumab. In the sequential therapy of advanced HCC with first-line and second-line drugs, the timing of treatment switch is very important. Generally, switching to a second-line targeted therapy drug is required for patients with progression on first-line drug therapy. However, the specific causes and patterns of disease progression should also be analyzed specifically. If the patient has disease progression due to insufficient dose caused by side effects of the first-line drug, dose recovery should be considered after the side effects are alleviated or tolerated, rather than therapy switching. Similarly, the pattern of progression on first-line therapy also influences the choice of subsequent therapy. If rapid disease progression occurs while the patient is receiving an adequate dose of first-line therapy drug, it should be switched to second-line drugs as soon as possible. However, if the tumor progresses slowly, it can be considered that the first-line drug is still partially effective and may be used in combination with an immune checkpoint inhibitor to improve the overall efficacy.