Objective To explore the effects of neoadjuvant chemotherapy on circulating tumor cells (CTC), serum tumor markers, angiogenesis indicators and life quality in patients with locally advanced esophageal cancer. Methods A total of 84 cases patients with locally advanced esophageal cancer admitted to Guang’an People’s Hospital from March 2016 to March 2019 were selected as the research objects, they were divided into the control group and the observation group according to the random number table method, each group with 42 cases. Patients in the control group were treated with radical resection of esophageal cancer, patients in the observation group were treated with neoadjuvant chemotherapy combined with radical resection of esophageal cancer, patients in both groups were followed up regularly for 2 years after surgery. The changes of CTC, serum tumor markers and angiogenesis indicators of patients in the two groups at admission, before surgery, and 3 months after surgery, the 2-year survival rate, distant metastasis rate and local recurrence rate after operation were compared. Results Compared with admission, the levels of CTC, serum cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA) and transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) levels of patients in the control group before operation increased, but the difference was not statistically significant (all P >0.05); the levels of the above indexes 3 months after operation decreased compared with before operation and admission, while the levels of CTC, serum CYFRA21-1, CA125, CEA, TGF-β1, VEGF, MMP-9 of patients in the observation group gradually decreased from admission to 3 months after operation, and the observation group was significantly lower than the control group before operation and 3 months after the operation; the survival rate of patients in the observation group was significantly higher than that of the control group, and the rates of distant metastasis and local recurrence were significantly lower than those of the control group 2 years after operation (all P <0.05). Conclusion Neoadjuvant chemotherapy combined with radical resection of esophageal cancer, can further reduce CTC levels and serum tumor marker levels of patients with locally advanced esophageal cancer, inhibit the tumor angiogenesis, improve patients’ survival rate, and prevent the distant metastasis and recurrence.