Objectives: Although unexpected conversion during Video-Assisted Thoracic Surgery (VATS) lobectomy is up to 23%, the effects on postoperative outcomes remain debatable. This retrospective study aimed: (i) to identify potential preoperative risk factors of VATS conversion to standard thoracotomy; (ii) to assess the impact of surgical experience in VATS lobectomy on conversion rate and patient health-related quality of life. Methods: We extracted detailed information on VATS lobectomy procedures performed consecutively (2014–2019). Predictors of conversion were assessed with univariable and multivariable logistic regressions. To assess the impact of VATS lobectomy experience, observations were divided according to surgeons’ experiences with VATS lobectomy. The impact of VATS lobectomy experience on conversion and occurrence of postoperative complications was evaluated using logistic regressions. The impact of VATS lobectomy experience on EuroQoL-5D (EQ-5D) scores at discharge was assessed using Tobit regressions. Results: A total of 11,772 patients underwent planned VATS for non-small-cell lung cancer (NSCLC), with 1074 (9.1%) requiring conversion to thoracotomy. The independent predictors at multivariable analysis were: FEV1% (OR = 0.99; 95% CI: 0.98–0.99, p = 0.007), clinical nodal involvement (OR = 1.43; 95% CI: 1.08–1.90, p = 0.014). Experienced surgeons performed 4079 (34.7%) interventions. Experience in VATS lobectomy did not show a relevant impact on the risk of open surgery conversion (p = 0.13) and postoperative complications (p = 0.10), whereas it showed a significant positive impact (p = 0.012) on EQ-5D scores at discharge. Conclusions: Clinical nodal involvement was confirmed as the most critical predictor of conversion. Greater experience in VATS lobectomy did not decrease conversion rate and postoperative complications but was positively associated with postoperative patient quality of life.