Objective To explore the predictive value of peripheral blood cells in the efficacy of neoadjuvant immunotherapy combined with chemotherapy for esophageal squamous cell carcinoma. Methods A retrospective study was conducted on patients with esophageal squamous cell carcinoma (clinical stages Ⅱ-Ⅳa) who underwent neoadjuvant immunotherapy combined with chemotherapy at the Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College from April 2020 to November 2023. According to whether the pathology was completely relieved after treatment, patients were divided into a pathological complete remission group and a pathological incomplete remission group. According to the CAP criteria for tumor pathological regression grading after neoadjuvant therapy, patients were divided into groups (TRG=0, 1 defined as good efficacy, TRG=2, 3 defined as poor efficacy). Results A total of 92 patients with esophageal squamous cell carcinoma were included, including 72 males and 20 females. The average age was 65.86±7.66 years. The complete remission of pathology was closely related to the number of lymphocytes in the blood before treatment (P=0.019). The AUC for predicting complete remission of esophageal squamous cell carcinoma after neoadjuvant immunotherapy combined with chemotherapy was 0.678, the maximum Yoden index was 0.328, and the optimal cutoff value was 1.845. The incidence of postoperative pulmonary infection in the group with incomplete pathological remission (25% vs. 5.6%, P=0.030) was higher than that in the group with complete pathological remission. According to the optimal cutoff value classification, there was a statistically significant difference (P<0.05) in the pathological N stage and pathological TNM stage between the two groups. The efficacy response was closely related to the number of red blood cells in the blood before treatment (P=0.009). The AUC for predicting TRG response after neoadjuvant immunotherapy combined with chemotherapy in esophageal squamous cell carcinoma was 0.669, the maximum Yoden index was 0.385, and the optimal cutoff value was 4.235. There were significant differences in postoperative pathological T staging (P=0.000), N staging (P=0.041), and TNM staging (P=0.000). According to the optimal cutoff value classification, there was a statistically significant difference in age (P=0.000) and hypertension (P=0.022) between the two groups. Conclusion Before neoadjuvant therapy, lymphocyte absolute value≥1.845 and red blood cell count<4.235 have good predictive effects on pathological complete remission and pathological response of esophageal squamous cell carcinoma after neoadjuvant immunotherapy combined with chemotherapy.