Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. The aim of this study was conducted a meta-analysis to assess the efficacy and safety of PD-1/PD-L1 inhibitors in patients with unresectable hepatocellular carcinoma (uHCC). A total of 1657 patients were included. The completed phase III trials with details data, such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects (AEs) were included. The pooled hazard ratio (HR) of OS and PFS were .75 (95% CI: .61-.92) and .74 (95% CI: .56-.97) with heterogeneity between PD-1/PD-L1 inhibitors groups and control groups. Sensitivity analysis revealed IMbrave-150 could be the most important factor of heterogeneity for OS, while CheckMate-459 was the main fact of heterogeneity for PFS. In addition, the relative risk (RR) of ORR and DCR were 2.43 (95% CI: 1.80-3.26) and 1.26 (95% CI: 1.11-1.43) with low heterogeneity in PD-1/PD-L1 inhibitors groups. The therapeutic effect of PD-1/PD-L1 inhibitors was better in females, Asia without Japan, BCLC status C and infected hepatitis groups. The RR of AEs from any cause and serious adverse events (SAEs) for patients receiving PD-1/PD-L1 inhibitors were 1.03 (95% CI: .93-1.13) and 1.13 (95% CI: .89-1.44), respectively. Pruritus was the most common AEs reported in 10% of patients or more (RR = 1.69, 95% CI: 1.33-2.15). In conclusion, PD-L1 inhibitor combined with anti-VEGF antibody could improve the prognosis of patients with uHCC. However, caution should be taken for AEs during patients receiving PD-1/PD-L1 inhibitors.