Patients with BRAF^V600E-mutated metastatic lung cancer benefit from both BRAF plus MEK inhibitors and immune checkpoint inhibitor (ICI)–chemotherapy. This study evaluated the cost-effectiveness of first-line ICI–chemotherapy compared with BRAF plus MEK inhibitors in these patients. This economic analysis, with a 15-year time horizon and an annual 3% discount, was conducted from the perspective of the healthcare sectors in Taiwan and the US. Simulated patients were entered into partitioned survival models upon initiation of first-line therapies. The model inputs were derived from the FRONT-BRAF study (progression-free/overall survival, adverse events, and subsequent therapies), insurance payments or retail prices (costs of drugs, physician visits, monitoring, adverse events, and end-of-life care), and a hospital cohort (health utility). Deterministic and probabilistic analyses were performed. The incremental cost-effectiveness ratios (ICERs) of ICI–chemotherapy compared with BRAF plus MEK inhibitors (Taiwan: $73,561/QALY; US: $290,279/QALY) exceeded the willingness-to-pay (WTP) thresholds (Taiwan: $70,000/QALY; US: $150,000/QALY). The drug costs of subsequent therapies and the utility values of the progressive-disease state were the major determinants of ICERs. In Taiwan, ICI–chemotherapy had a 41.0% probability of being cost-effective at the WTP threshold. ICI–chemotherapy had a higher probability of being cost-effective than BRAF plus MEK inhibitors when the WTP exceeded $300,000/QALY in the US. Our analysis suggests that, despite the longer survival of first-line ICI–chemotherapy compared with BRAF plus MEK inhibitors, ICI–chemotherapy is not a cost-effective strategy for patients with BRAF^V600E-mutated metastatic lung cancer.