This study was aimed to evaluate the cost-effectiveness of pembrolizumab with chemotherapy (pembrolizumab combination therapy) and compare it with standard-of-care platinum-based chemotherapy (chemotherapy alone) as a first-line treatment for metastatic nonsquamous NSCLC from the perspective of Taiwan's third-party-payer public health-care system. We used a partitioned survival model with an estimated time horizon of 10 years. The partitioned survival model uses Kaplan-Meier estimates of progression-free and overall survival from the KEYNOTE-189 clinical trial. The quality-adjusted life-year (QALY) values were based on utility values by progression status calculated from the KEYNOTE-189 trial. This study examined costs related to treatment regimens, disease management, second-line therapy, end-of-life care, and adverse event management. Cost and utility were discounted at 3% per year. Probabilistic and deterministic sensitivity analyses were performed to test the robustness of the results. The willingness-to-pay threshold was set at 3 × Taiwan's gross domestic product (GDP), equivalent to NT$2,788,290. In the base-case scenario, pembrolizumab combination therapy resulted in an expected gain of 0.89 QALYs and an incremental cost of NT$2,201,203 relative to chemotherapy alone. The ICER was NT$2,478,601/QALY. In the analysis of the PD-L1 tumor proportion score (TPS) ≥ 50% subgroup, the patients who received pembrolizumab combination therapy gained 1.12 QALYs more than those who received chemotherapy alone, and the incremental cost was NT$2,522,528. Therefore, the ICER for this subset of patients was NT$2,258,358/QALY. In conclusion, pembrolizumab combination therapy is a cost-effective option for first-line treatment of metastatic nonsquamous NSCLC. The relative cost-effectiveness of pembrolizumab combination therapy is greatest for patients with PD-L1 TPS ≥50%.