Objectives: Residual postoperative pleural space (RPPS) is a common event after pulmonary lobectomy. Uniportal video-assisted thoracoscopic surgery (VATS) lobectomy has been associated with a higher incidence of RPPS. This study aims to evaluate the incidence, the predictors, and potential clinical implications of RPPS following Uniportal VATS lobectomy. Methods: Patients who underwent Uniportal VATS lobectomy, without any previous neoadjuvant treatment, from June 2016 to March 2020, were retrospectively analyzed. RPPS was assessed using the last chest X-Ray prior to discharge and measured by Collins method (%). Results: Among 492 patients who underwent Uniportal VATS lobectomy, 325 (66.1%) developed RPPS. The mean RPPS volume measured by the Collins method was 15.46 ± 8.59% (vs. Collins = 4.2% in no-PRPS). An RPPS > 10.5% of Collins was significantly associated with a higher risk of postoperative air leak (AUC: 0.69, sensitivity: 69%, specificity: 54%, p < 0.001). Multivariable analysis identified the following predictors of RPPS > 10.5%: right-sided surgery (p < 0.001), upper lobectomy (p = 0.01), and prolonged air leak (p = 0.003). Patients with RPPS had a higher risk of only radiologically visible postoperative subcutaneous emphysema on the final chest X-ray (p = 0.041) and were more frequently discharged with a chest tube connected to a Heimlich valve (p < 0.001). Within 90 days post-discharge, 24 (4.9%) patients were readmitted due to increased RPPS (1.4%, requiring drainage in 5 cases [1%]), progression of subcutaneous emphysema (1.6%), and pleural effusion (1.8%, requiring drainage in 6 cases [1.2%]). However, RPPS was not associated with an increased overall risk of postoperative complications (p = 0.31) or 90-day readmission (p = 0.43). Conclusions: RPPS is a common occurrence following Uniportal VATS lobectomy but is not associated with clinically significant complications. The current study findings identified BMI, active smoking, right-sided surgery, and prolonged air leak as significant predictors of RPPS.