Objective To investigate the efficacy of sindilizumab combined with neoadjuvant chemotherapy in the treatment of locally advanced esophageal cancer. Methods A total of 146 patients with esophageal cancer were included in this study, all of whom were from Anyang Cancer Hospital from May 2021 to May 2024. According to different treatment methods, all patients were divided into control group (73 cases, Albumin-bound paclitaxel combined with cisplatin) and study group (73 cases, Sindilizumab combined with albumin-bound paclitaxel and cisplatin). All patients underwent minimally invasive radical resection of esophageal cancer after receiving neoadjuvant therapy. Perioperative indexes, short-term efficacy, pathological remission, serum tumor markers before and after treatment, and the occurrence of adverse reactions were compared between the two groups. Results The R0 removal rate in the study group was 93.15%, which was higher than that in the control group (68.50%) (χ2=14.317, P<0.05). The ORR and DCR rates in the study group (76.71% and 98.63%) were higher than those in the control group (41.10% and 83.60%) (χ2=19.127, 10.217, P<0.05). Eight patients in the control group achieved pCR, and the pCR rate was 10.96%, while the pCR rate in the study group was 35.62% (26/73). After comparison, the PCR rate in the study group was higher than that in the control group, with statistical significance (χ2=12.422, P<0.05). After treatment, the levels of serum tumor markers in 2 groups were lower than before treatment, and those in the study group were lower (t=14.665, 2.055, 28.211, P<0.05). There was no significant difference in the total incidence of adverse drug reactions between the two groups (χ2=3.318, P>0.05). Conclusion Sindilizumab combined with neoadjuvant chemotherapy can improve perioperative R0 resection rate, ORR and DCR rates, and reduce serum tumor marker levels in patients with locally advanced esophageal cancer, with good safety.