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Simple Summary: In cases of advanced lung cancer after neoadjuvant chemotherapy (nCT), the role of uniportal video-assisted thoracoscopic surgery (U-VATS) is still questionable, with concerns about safety, technical feasibility, and oncological completeness. The aim of this retrospective study was to assess the impact of nCT on patients who had undergone U-VATS anatomic lung resections for lung cancer. We compared the short-term outcomes of 60 patients with case-matched counterparts (treated by surgery alone) selected by propensity score analysis, finding that U-VATS after nCT is a feasible approach with a similar rate of cardiopulmonary complications, length of stay, and readmission when compared with the control group. However, it is still a challenging surgery due to the great technical complexity, which is responsible for the higher incidence of conversion. Background: The advantages of video-assisted thoracic surgery (VATS) are well-recognized in several studies. However, in the cases of advanced lung cancer after neoadjuvant chemotherapy (nCT), the role of VATS is still questionable, with concerns about safety, technical feasibility, and oncological completeness. The aim of this study was to assess the impact of nCT on patients who had undergone uniportal VATS (U-VATS) anatomic lung resections for lung cancer, by comparing the short-term outcomes of patients after nCT with case-matched counterparts (treated by surgery alone). Methods: We performed a retrospective, comparative study enrolling 927 patients (nCT: 60; non-nCT:867) who underwent U-VATS anatomic lung resections from 2014 to 2020 in two centers. Data were collected in a shared database with standardized variables' definition. Propensity score matching using 15 baseline preoperative patients' characteristics was performed in order to minimize selection-confounding factors between the two groups, which then were directly compared in terms of perioperative outcomes. Results: After propensity score matching, two groups of 60 patients had been defined. The nCT-group had a higher conversion rate compared to the control group (13.3% vs. 0%, p = 0.003) without an increase in operation time or cardiopulmonary complications. In addition, no differences between the two groups were recorded in terms of prolonged air leaks, length of stay, and readmission. Conclusions: U-VATS after nCT is a feasible approach, showing a similar rate of cardiopulmonary complications and length of stay when compared with the control group. However, it remains a challenging surgery due to its great technical complexity as well as the clinical status of the patients. [ABSTRACT FROM AUTHOR]