The purpose of this study was to evaluate the safety and efficacy of Pembrolizumab combined with chemotherapy in neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma. Patients with locally advanced esophageal squamous cell carcinoma who underwent neoadjuvant therapy in our department from October 2021 to September 2022 were selected. They received two cycles of chemotherapy combined with Pembrolizumab before surgery. A total of 32 patients were enrolled, 29 patients subsequently underwent surgery, the pCR rate was 27.6% (8/29). Patients with a positive CPS score had a higher probability of pCR (46.2% vs. 12.5%, p < 0.05). CD8+ cell rate increased after neoadjuvant therapy, and the difference was statistically significant compared to before treatment (p < 0.001).The clinical efficacy of immune checkpoint inhibitors combined with chemotherapy for neoadjuvant therapy in patients with advanced esophageal squamous cell carcinoma is definite, and the safety and feasibility are high.