Background: Hepatocellular carcinoma has a high mortality rate, with an overall 5-year survival of less than 20%. Whether the use of immune checkpoint inhibitors (ICI) is superior to tyrosine kinase inhibitors (TKI) as a first-line therapy remains unclear. Methods: We performed a systematic review and meta-analyses of randomized clinical trials (RCTs) to compare ICI, in monotherapy or combined with TKI or anti-VEGF monoclonal antibody in naïve treatment. We searched Embase, PubMed and Cochrane Library databases from inception to November 2022. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS), Overall Response Rate (ORR) and Treatment Related Adverse Events (TRAE). Using a random-effects model, statistical analysis was performed with RevMan 5.4 version for proportions and risk ratios for binary outcomes from comparative studies. Results: We included 10 RCTs comprising 6097 patients in the final analysis, 2554 in ICI monotherapy, 1096 in ICI with anti-VEGF and 2447 in ICI with TKI. The use of ICI, alone or in combination therapy, was associated with a better OS (HR 0.77; 95% CI 0.69–0.85; p< 0.00001; I²=46%) and PFS (HR 0.77; 95% CI 0.64-0.92, p=0.005; I²= 85%). In the ICI monotherapy subgroup, there was a statistical difference to TKI in OS (HR 0.82; 95% CI 0.75-0.91; p=0.0001; I² = 0%). Although there was a higher ORR in all ICI groups (RR 2.56; 95% CI 1.89-3.46; p<0.00001, I²=68%), TRAE Grades 3-4 (RR 0.85; 95% CI 0.61-1.18; p=0.33; I²=96%) presented no difference when compared with TKI. Conclusions: Our findings suggest that the use of ICI, alone or in combination with TKI or anti-VEGF, is a superior option for first-line therapy for advanced hepatocellular carcinoma, improving OS, PFS, and ORR without increasing treatment toxicity. These results are important for guiding clinical decision-making and further research in this field.