Background: Hepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality. Sorafenib used to be the main treatment for unresectable HCC patients. However, regimens based on immune checkpoint inhibitors (ICIs) have attracted attention in recent years because of their reported benefits. This study aimed to evaluate the efficacy and safety of monotherapy and combination therapy of ICIs as first-line treatment for unresectable HCC patients by conducting a systematic review, meta-analysis, and network meta-analysis. Methods: Studies published up to 11st August 2022 were searched from 4 commonly used databases, including PubMed, Web of Science, Embase, and Clinical trials.gov. All eligible clinical trials were included. Data about reported objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were extracted. Results: Of the 8579 studies retrieved, 24 met the inclusion criteria. In patients with unresectable HCC taking ICIs-based therapy as first-line treatment, the pooled result of median PFS and median OS was 5.76 months (95% CI 4.82–6.69) and 16.35 months (95% CI 15.19–17.51) The ORR and DCR were 25.1% (95% CI 20.8–29.5%) and 75.2% (95% CI 70.3–80.2%) measured by RECIST v1.1 or 40.2% (95% CI 31.7–48.6%) with 75.2% (95% CI 68.3–82.1%) measured by mRECIST v1.1. Compared to sorafenib, ICIs-based therapy significantly prolonged OS. The combination treatment of sintilimab plus IBI305 had the highest ORR, while atezolizumab plus bevacizumab had the highest DCR. The pooled incidence of any grade TRAEs was 82.3% (95% CI 73.9–90.7%), with highest incidence appeared in dysphonia. Conclusions: This study demonstrated that first-line ICIs-based therapies could provide survival benefits for patients with unresectable HCC, with manageable TRAEs. The potential of combination treatment to become the new treatment trend in clinical practice is promising.