Background The role of video-assisted thoracoscopic surgery for the treatment of non-small-cell lung cancer after neoadjuvant chemotherapy remains controversial. The aim of this study is to demonstrate the reliability of video-assisted lobectomy compared to the open approach by evaluating perioperative and long-term outcomes. Methods In this retrospective, multicentric study from January 2010 to December 2018, we included all patients with non-small-cell lung cancer who underwent lobectomy through the video-assisted or open approach after neoadjuvant chemotherapy. The perioperative outcomes, including data concerning the feasibility of the surgical procedure, the occurrence of any medical and surgical complications and long-term oncological evidence, were collected and compared between the two groups. To minimize selection bias, propensity score matching was performed. Results A total of 286 patients were enrolled: 193 underwent thoracotomy lobectomy, and 93 underwent VATS lobectomy. The statistical analysis showed that surgical time ( P  < 0.001), drainage time ( P  < 0.001), days of hospitalization ( P  < 0.001) and VAS at discharge ( P  = 0.042) were lower in the VATS group. The overall survival and disease-free survival were equivalent for the two techniques on long-term follow-up. Conclusions VATS lobectomy represents a valid therapeutic option in patients affected by non-small-cell lung cancer after neoadjuvant chemotherapy. The VATS approach in our experience seems to be superior in terms of the perioperative outcomes, while maintaining oncological efficacy.