Objective To evaluate the safety and efficacy of neoadjuvant therapy followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal cancer. Methods We retrospectively analyzed clinical data of 56 consecutive patients with locally advanced esophageal cancer treated by neoadjuvant therapy followed by surgery in our hospital between January 2015 and December 2016. There were 51 males and 5 females. The patients were divided into 2 groups. Neoadjuvant therapy followed by open surgery esophagectomy group was as an OE group with 25 patients aged 61 (50-73) years. And neoadjuvant therapy followed by MIE was as a MIE group with 31 patients aged 60 (55-79) years. Results The pathologic complete response (pCR) rate of 28 patients with neoadjuvant concurrent chemoradiotherapy was significantly higher than that of 28 patients with neoadjuvant chemotherapy (21.4% vs. 10.7%, P<0.05). The operation time, intraoperative blood loss, R2 rate and the number of lymph nodes dissection in the MIE group were obviously better than those of the OE group with statistical differences (P<0.05). However, there was no significant difference in the number of resected lymph nodes along the bilateral recurrent laryngeal nerves and lymph node metastasis rate (P>0.05) between the two groups. The incidence of postoperative respiratory complications in the MIE group was lower than that of the OE group (P=0.041). There was no significant difference between the two groups in the incidence of other complications, re-operation, re-entry to ICU, median length of stay or perioperative deaths (P>0.05). There was only one patient with neoadjuvant concurrent chemoradiotherapy in the OE group died due to gastric fluid asphyxia caused by trachea-esophageal fistula. Conclusion Neoadjuvant therapy followed by MIE for locally advanced esophageal cancer is safe and feasible. The oncological outcomes seem comparable regardless of OE.