Objective To investigate the effect of thoraco-laparoscopic esophagectomy on postoperative immune function of patients with esophageal carcinoma. Methods Eighty-one patients undergoing radical esophagectomy in our hospital between January, 2017 and December, 2019 were enrolled in this study. According to the surgical approach, the patients were divided into endoscopic group (41 cases) and open surgery (3 incisions) group (40 cases). The immunological indicators (CD3+ , CD4+ , CD8+ , and CD4+ /CD8+ ratio) of the patients were analyzed using double antibody sandwich enzyme-linked immunosorbent assay at 1 day before the surgery and on days 1, 4 and 7 after the surgery. The plasma levels of interleukin 6 (IL-6) and cortisol, β-endorphin (β-EP) level, white blood cell count (WBC) and C-reactive protein (CRP) levels of the patients were measured before and on days 1 and 7 after the operation. Results No death occurred in either of the group after the operation. On days 4 and 7 after the operation, CD3+ , CD4+ , CD8+ , and CD4+ /CD8+ ratio were significantly higher in patients undergoing thoraco-laparoscopic surgery than in those receiving open surgery (P<0.05). In both groups, the levels of cortisol, β-EP, WBC, CRP and IL-6 measured on days 1 and 7 postoperatively were significantly different from those before the operation (P<0.05). At all the indicated postoperative time points, all the measured indicators, with the exception of IL-6 levels on postoperative day 7, which were comparable between the two groups, were significantly higher in the open surgery group than in the endoscopic group (P<0.05). Conclusion Thoraco-laparoscopic resection of esophageal cancer can reduce postoperative secretion of proinflammatory factors, alleviate inflammatory responses, and promote the recovery of immune functions to accelerate postoperative recovery of the patients.