BackgroundPD-1/PD-L1 inhibitors combined with chemotherapy have improved survival outcomes in patients with driver mutation–negative non-squamous non-small cell lung cancer (non-sqNSCLC). However, the comparative efficacy, safety, and economic value of available PD-1/PD-L1 inhibitor–based regimens remain uncertain in China.MethodsWe conducted a network meta-analysis to indirectly compare the efficacy and safety of 14 first-line treatment regimens, including 13 PD-1/PD-L1 inhibitor–based chemotherapy regimens and chemotherapy alone, in patients with driver mutation–negative non-sqNSCLC. Clinical evidence was subsequently integrated into a Markov model with a 10-year time horizon and 3-week cycles to evaluate cost-effectiveness from the perspective of the Chinese healthcare system. Transition probabilities were derived from reconstructed survival curves using parametric survival models. The primary economic outcomes included total costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). Deterministic and probabilistic sensitivity analyses were performed to assess model robustness.ResultsThe network meta-analysis demonstrated that toripalimab, sintilimab, and pembrolizumab combined with chemotherapy provided superior efficacy and favorable safety among 13 PD-1/PD-L1 inhibitors with chemotherapy for non-sqNSCLC. In the cost-effectiveness analysis, toripalimab with chemotherapy achieved 2.583 QALYs at a total cost of 39,232.33.Anditwascost−effectivecomparedwithchemotherapyalone,camrelizumab−,tislelizumab−,andsintilimab−basedchemotherapyregimens,withICERsrangingfrom39,232.33. And it was cost-effective compared with chemotherapy alone, camrelizumab-, tislelizumab-, and sintilimab-based chemotherapy regimens, with ICERs ranging from 10,624.47 to 16,120.12perQALY,allbelowthewillingness−to−paythresholdof16,120.12 per QALY, all below the willingness-to-pay threshold of 41,859/QALY. Compared with chemotherapy alone, camrelizumab, tislelizumab, sintilimab with chemotherapy were cost-effective, with ICERs of 28,813.78/QALY,28,813.78/QALY, 19,278.47/QALY, and $20,315.01/QALY, respectively. PFS and PD utilities were key drivers of cost-effectiveness, while drug costs predominantly influenced regimens with ICERs.ConclusionAmong currently available first-line treatment strategies for driver mutation–negative non-sqNSCLC in China, toripalimab and sintilimab combined with chemotherapy demonstrated favorable clinical and economic profiles. These findings provide evidence to support treatment selection, reimbursement decisions, and healthcare resource allocation in clinical practice.