Background:Assess the effectiveness and safety of treatment options atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib in clinical practice for patients with advanced hepatocellular carcinoma (HCC) patients.Methods:To compare the effectiveness of Atez/Bev and lenvatinib in treating advanced HCC, we systematically searched the PubMed, EMBASE, and Web of Science databases. We utilized Review Manager 5.3 to extract and analyze the data.Results:The present systematic review included 8 nonrandomized studies comprising a total of 6628 cases. There was no significant difference in 0.5-, 1-, 1.5-year OS rates and 0.5-, 1-year PFS rates between the 2 groups. However, patients with HCC caused by viral hepatitis would benefit more from the Atez/Bev therapy (hazard ratio = 0.75, 95% confidence interval: 0.63–0.89) but patients with a Child–Pugh class B liver function would benefit more from lenvatinib (hazard ratio = 1.70, 95% confidence interval: 1.07–2.70). At the same time, there are no major differences in safety between the 2 treatment options.Conclusion:Our study did not find any significant difference in effectiveness and safety between Atez/Bev and lenvatinib. However, Additional verification is required to determine whether these 2 therapeutic approaches have varying effects on distinct populations.