For patients with metastatic non-small cell lung cancer (mNSCLC), next-generation sequencing (NGS) biomarker testing has been associated with a faster time to appropriate targeted therapy and more comprehensive testing relative to polymerase chain reaction (PCR) testing. However, the impact on payer costs and clinical outcomes during patients' treatment journeys has not been fully characterized. To assess the costs and clinical outcomes of NGS vs PCR biomarker testing among patients with newly diagnosed de novo mNSCLC from a US payers' perspective. A Markov model assessed costs and clinical outcomes of NGS vs PCR testing from the start of testing up to 3 years after. Patients entered the model after receiving biomarker test results and then initiated first-line (1L) targeted or nontargeted therapy (immunotherapy and/or chemotherapy) depending on actionable mutation detection. A few patients with an actionable mutation were not detected by PCR and inappropriately initiated 1L nontargeted therapy. At each 1-month cycle, patients could remain on treatment with 1L, progress to second line or later (2L+), or die. Literature-based inputs included the rates of progression-free survival (PFS) and overall survival (OS), targeted and nontargeted therapy costs, total costs of testing, and medical costs of 1L, 2L+, and death. Per patient average PFS and OS as well as cumulative costs were reported for NGS and PCR testing. In a modeled population of 100 patients (75% commercial and 25% Medicare), 45.9% of NGS and 40.0% of PCR patients tested positive for an actionable mutation. Relative to PCR, NGS was associated with $7,386 in savings per patient (NGS = $326,154; PCR = $333,540) at 1 year, driven by lower costs of testing, including estimated costs of delayed care and nontargeted therapy initiation before receiving test results (NGS = $8,866; PCR = $16,373). Treatment costs were similar (NGS = $305,644; PCR = $305,283). In the PCR cohort, the per patient costs of inappropriate 1L nontargeted therapy owing to undetected mutations were $6,455, $6,566, and $6,569 over the first 1, 2, and 3 years, respectively. Relative to PCR testing, NGS was associated with $4,060 in savings at 2 years and $1,092 at 3 years. Patients who initiated 1L targeted therapy had an additional 5.4, 8.8, and 10.4 months of PFS and an additional 1.4, 3.6, and 5.3 months of OS over the first 1, 2, and 3 years, respectively, relative to those who inappropriately initiated 1L nontargeted therapy. In this Markov model, as early as year 1, and over 3 years following biomarker testing, patients with newly diagnosed de novo mNSCLC undergoing NGS testing are projected to have cost savings and longer PFS and OS relative to those tested with PCR.