Objective To systematically evaluate the efficacy and safety of a combination regimen of PD-1/PD-L1 immune checkpoint inhibitors in the first-line treatment of advanced non-small cell lung cancer. Methods Randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitor combination regimen in the first-line treatment of advanced non-squamous NSCLC were systematically retrieved from the Chinese and English electronic databases from inception to September 2023. The combination regimen includes PD-1/PD-L1 inhibitor+chemotherapy, PD-1/PD-L1 inhibitor+chemotherapy+anti-angiogenic agents (bevacizumab), and PD-1/PD-L1 inhibitor+CTLA4 inhibitor (ipilimumab). The network meta-analysis was performed using StataMP16.0 and R4.2.0 software. ResultsA total of 13 RCTs were collected, including 7 764 patients. In terms of effectiveness, compared with chemotherapy, several regimens improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Among them, toripalimab (Tor) plus chemotherapy (CT) may be associated with the best OS, and nivolumab plus bevacizumab and chemotherapy (Niv+Bev+CT) may provide the best PFS. Pembrolizumab (Pem) combined with CT was associated with the best treatment regimen for improving ORR. In terms of safety, except sintilimab (Sin) and Pem, the incidence of grade≥3 adverse events of all treatment regimens was significantly higher than that of chemotherapy (P<0.05). The incidence of AEs≥3 grade in Cam+CT was higher than that in Sin+CT (OR=0.44, 95%CI 0.25-0.80) and Pem+CT (OR=0.52, 95%CI 0.31-0.88). And the incidence of ≥3grade AEs in Atezolizumab (Ate) +Bev+CT (OR=2.32, 95%CI 1.14-4.71; OR=1.97, 95%CI 1.02-3.79) was also higher than that in Sin+CT and Pem+CT (P<0.05). Conclusion In non-squamous NSCLC patients, PD-1 inhibitor combined with chemotherapy can bring more benefits to advanced NSCLC patients than chemotherapy alone.