Objective To investigate the perioperative differences between video-assisted thoracoscopic surgery (VATS) and thoracotomy after neoadjuvant therapy in patients with non-small cell lung cancer (NSCLC). Methods Clinical data of NSCLC patients who underwent VATS or thoracotomy after neoadjuvant therapy at Shanghai Pulmonary Hospital from June 2020 to May 2022 were retrospectively collected. Perioperative outcomes were compared between the two groups.Results A total of 260 patients were enrolled, 184 patients (70.8%) underwent VATS and 76 patients (29.2%) underwent thoracotomy. After propensity matching there were 113 patients (62.4%) in the VATS group and 68 patients (37.6%) in the thoracotomy group.VATS had similar lymph node dissection ability and postoperative complication rate as thoracotomy (P>0.05), with the advantage of having shorter operative time (146 mL vs. 165 mL, P=0.006), less intraoperative blood loss (50 mL vs. 100mL, P<0.001), lower intraoperative blood transfusion rate (0% vs. 7.4%, P=0.011), less 3-day postoperative drainage (250 mL vs. 350 mL, P=0.011; 180 mL vs. 250 mL, P=0.002; and 150 mL vs. 235 mL, P<0.001), and postoperative drainage time (9.34 d vs. 13.84 d, P<0.001) and postoperative hospitalization time (6.19 d vs. 7.94 d, P= 0.006). Conclusion VATS after neoadjuvant therapy for lung cancer is safer than thoracotomy and results in better postoperative recovery.