Objective: The purpose of this study was to estimate the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods: A Markov model was developed to simulate the outcomes and direct medical costs of osimertinib or standard EGFR-TKI in the first-line treatment of patients with previously untreated EGFR-mutated advanced NSCLC. Individual patient survival data were extracted from the FLAURA randomized clinical trial. Clinical costs and utilities' input estimates were collected from the local hospital and available literature reports. The quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit (INMB), and incremental net health benefit (INHB) were calculated for the two treatment strategies over a 10-year lifetime horizon. In addition, one-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to test the robustness of the model. Results: On baseline analysis, osimertinib achieved additional 0.39 QALYs and $15,443.78 incremental costs compared with standard EGFR-TKI (gefitinib or erlotinib), which resulted in the ICER of $39,369.53/QALY. The INMB was -$755.11, and the INHB was -0.02 QALYs at a WTP threshold of $37,663.26/QALY in China. The one-way sensitivity analysis showed that the utility of PFS had the strongest association with the ICER. Osimertinib had approximately 46.4% probability of being cost-effective at the WTP threshold of $37,663.26/QALY. Conclusion: First-line osimertinib therapy might not be cost-effective in China for patients with EGFR-mutated advanced NSCLC compared with standard EGFR-TKI based on its current marketed price. A significantly more favorable cost-effectiveness could be achieved when the price of osimertinib was reduced by 5%.