Objective: To evaluate the cost–effectiveness of serplulimab as first-line treatment for patients with advanced esophageal squamous cell carcinoma from the perspective of the Chinese healthcare system. Materials & methods: A partitioned survival model was created to evaluate costs and health outcomes. The model's robustness was evaluated using one-way and probabilistic sensitivity analyses. Results: Serplulimab demonstrated an incremental cost–effectiveness ratio of $104,537.375/quality-adjusted life-year in the overall population group. Subgroup analysis showed that serplulimab had incremental cost–effectiveness ratios of $261,750.496/quality-adjusted life-year and $68,107.997/quality-adjusted life-year in the populations with PD-L1 1 ≤ combined positive score <10 and PD-L1 combined positive score ≥10, respectively. Conclusion: Incremental cost–effectiveness ratios of serplulimab therapy were found to exceed the willingness-to-pay threshold of $37,304.34. Thus, serplulimab is not cost-effective compared with chemotherapy as a first-line treatment for esophageal squamous cell carcinoma patients.