The study of DESTINY-Lung01 and DESTINY-Lung02 demonstrated the favorable efficacy and optimal dosage of trastuzumab deruxtecan (T-DXd) in managing the human epidermal growth factor receptor 2 (HER2)-mutant non-small cell lung cancer (NSCLC) patients who had received previous treatment. The study sought to assess the cost-effectiveness of T-DXd in both the United States (US) and Chinese healthcare systems. Markov models were developed to evaluate the overall cost, incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALYs), and life years (LYs) of treatment with T-DXd compared with docetaxel, nivolumab, and pyrotinib for patients in the US and China. The level of willingness-to-pay (WTP) in the US and China is 150,000/QALYs and 32,517/QALYs, respectively. Sensitivity analyses were carried out to ensure the precision of the model. T-DXd yielded additional QALYs of 0.63 and 0.06 with an ICER of $338997.84 and $1437258.33 per QALY, respectively, in the US compared to the docetaxel and nivolumab regimens. And T-DXd yielded additional QALYs of 0.63, 0.06, and 0.13 with an ICER of $137959.45, $623805.93, and $515447.12 per QALY, respectively, in China compared to the docetaxel, nivolumab, and pyrotinib regimens. Sensitivity analysis showed that the cost of drugs is the most influential factor. T-DXd provides substantial therapeutic benefit for NSCLC patients with HER2 mutations who have had previous treatment but is not deemed cost-effective in either the US or China when compared to docetaxel, nivolumab, and pyrotinib. Price reduction is perhaps the main way to make T-DXd cost-effective.