OBJECTIVE: A meta-analysis evaluated the efficacy and safety of immune checkpoint inhibitors in combination with targeted agents for first-line treatment of advanced unresectable hepatocellular carcinoma. METHODS: China Knowledge, Wanfang Data, China Clinical Trials Registry, PubMed, ClinicalTrials. gov, and Cochrane databases were searched for eligible studies up to April 24, 2024. Managing literature with NoteExpress evaluates the quality of the included literature, and performs Meta-analysis with RevMan 5.4.1. Treatment effects were quantified using hazard ratios (HR) for survival endpoints and relative risk (RR) for response rates. RESULTS: Five studies (3,058 participants) were included. Compared to the monotherapy group, the OS (HR 0.71, P<0.0001), PFS (HR 0.64, P<0.00001), ORR (RR 2.79, P<0.0001), and DCR (RR 1.22, P=0.004) were more significant in the combination therapy group. However, ≥grade3 TRAEs (HR 1.24, P=0.007) were lower in the monotherapy group, and no significant differences were observed in any grade of TRAEs (RR 1.03, P=0.09). The subgroup analysis indicated that compared with other combined treatments, the OS (HR 0.57, P<0.0001), PFS (HR 0.56, P<0.00001), and ORR (RR 5.05, P < 0.0001) in the bevacizumab+PD-1 inhibitor group were significantly different, whereas the DCR (RR 1.13, P = 0.06) was not significantly different. CONCLUSION: In the study that combined ICIs with targeted agents for advanced HCC, bevacizumab+PD-1 inhibitors were superior. PD-L1 inhibitor + TKI therapy is safer for patients with uncontrolled hypertension. First-line systemic therapy with targets was effective and unaffected by the prior local therapy. AFP level can serve as an indicator for screening therapeutic regimens.