Objective: To investigate the clinical efficacy of lenvatinib and sorafenib as first-line molecular targeted drugs in the treatment of advanced hepatocellular carcinoma. Methods: Through searching PubMed, Web of Science, Cochrane, CNKI, Wanfang, and other databases, all the literatures on the comparison of clinical efficacy of lenvatinib and sorafenib as first-line molecular targeted drugs in the treatment of advanced hepatocellular carcinoma were collected. According to the established criteria for inclusion and exclusion of literature, 2 research participants conducted literature screening, data sorting, and literature evaluation. The evaluation indicators include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and incidence of serious adverse reactions. Meta-analysis was performed using RevMan 5.3 software for the included studies. Results: A total of 7 articles with 2 419 observers (1 060 cases in the lenvatinib group and 1 359 cases in the sorafenib group) were included. Meta-analysis showed that PFS (HR =0.63, 95%CI: 0.55 to 0.73, Z=6.54, P<0.001) and ORR (OR =7.48, 95%CI: 3.29 to 16.98, Z=4.81, P<0.001) were superior in the lenvatinib group compared with the sorafenib group; serious adverse events occurred more in the lenvatinib group (OR =1.24, 95%CI: 1.03 to 1.50, Z=2.29, P=0.02) than those in the sorafenib group; there was no statistically significant difference in OS (HR =0.88, 95%CI: 0.78 to 1.00, Z=1.89, P=0.06) between the 2 groups. Conclusion: In patients with advanced hepatocellular carcinoma, compared with sorafenib, lenvatinib can prolong PFS and improve ORR, but the OS of patients is not prolonged and more serious adverse reactions occur.