Objective A randomized, multicenter, open-label, phase III trial (IMforte) demonstrated that lurbinectedin combined with atezolizumab significantly prolonged overall survival and progression-free survival in patients with extensive-stage small cell lung cancer (ES-SCLC) compared with atezolizumab alone. This study aimed to evaluate the cost-effectiveness of lurbinectedin combined with atezolizumab as first-line treatment for ES-SCLC from the perspective of the United States. Methods Based on the IMforte trial, a Markov model was developed to simulate the disease progression of ES-SCLC, including three health states: progression-free survival (PFS), disease progression (PD), and death. The model simulation period was 10 years with a 3-week cycle. The model used cost and quality-adjusted life years (QALYs) as output indicators, and the incremental cost-effectiveness ratio (ICER) was calculated through cost-effectiveness analysis to assess the economic feasibility of lurbinectedin combined with atezolizumab compared with atezolizumab alone. Sensitivity analysis and scenario analysis were conducted to test the robustness of the model. Results Compared with atezolizumab alone, the lurbinectedin combined with atezolizumab group had an additional cost of $85,854.15 and an incremental benefit of 0.2 QALYs. The lurbinectedin combined with atezolizumab group was not cost-effective compared with the atezolizumab group, with an ICER of $429,270.75/QALY, exceeding the willingness-to-pay threshold of $150,000. The model was most sensitive to the cost and PFS utility value of the lurbinectedin combined with atezolizumab group. Conclusion From the perspective of US payers, lurbinectedin combined with atezolizumab is not a cost-effective option for first-line treatment of ES-SCLC.