Objective To systematically review the efficacy and safety of immune checkpoint inhibitors (ICIs) as first-line treatment for advanced non-small cell lung cancer (NSCLC). MethodsTo collect clinical randomized controlled trials of ICIs for the first-line treatment of patients with NSCLC, computer searches were conducted on PubMed, The Cochrane Library, and EMbase databases. The search time frame was inception to January 2023. A meta-analysis was performed using Revman 5.4 software. ResultsTwelve clinical studies were included, all of which were assessed as high-quality literature with a total of 7 121 patients. Meta-analysis showed that the first-line treatment of NSCLC patients with ICIs significantly improved median overall survival (OS) (HR=0.72, 95%CI 0.64 to 0.80, P < 0.000 01), prolonged median progression-free survival (PFS) (HR=0.65, 95%CI 0.53 to 0.78, P<0.000 01), and improved objective response rate (ORR) (RR=1.52, 95%CI 1.28 to 1.79, P<0.000 01), compared to chemotherapy. Subgroup analysis showed that the ICIs combination therapy group significantly improved OS, PFS, and ORR in NSCLC patients compared to the ICIs monotherapy group. In terms of safety, the ICIs group had a lower risk of treatment-related adverse events (TRAEs) of any grade and grade 3-5 TRAEs than the chemotherapy group. However, the ICIs group had a higher incidence of TRAEs leading to treatment cessation than the chemotherapy group. Subgroup analysis showed that the incidence of any grade TRAEs, grade 3-5 TRAEs, leading to treatment discontinuation TRAEs was higher in the immune combination therapy group than in the immune monotherapy group. ConclusionThe first-line treatment of NSCLC patients with ICIs inhibitors significantly improved OS, PFS, and ORR compared to chemotherapy. Immune-combination chemotherapy significantly improved the outcomes of NSCLC patients, compared to immune monotherapy, but patients were at a higher risk of TRAEs.