Background <p>This study aimed to evaluate the impact of pneumonectomy after neoadjuvant therapy by assessing postoperative outcomes, survival prognosis, and recurrence patterns.</p> Methods <p>A retrospective analysis of patients with non-small cell lung cancer (NSCLC) who underwent pneumonectomy between January 2017 and December 2022 was performed. The patients were divided into two groups based on whether they received neoadjuvant therapy, resulting in the neoadjuvant therapy group and the non-neoadjuvant therapy group. Propensity score-matching was performed to balance the cohorts. Perioperative outcomes, survival outcomes, and recurrence patterns were compared between the two groups.</p> Results <p>The entire cohort comprised 455 patients. Using a 2:1 propensity score-matching method, 229 patients in the non-neoadjuvant therapy group and 137 patients in the neoadjuvant therapy group were enrolled in the subsequent analysis. Univariate logistic regression analysis showed that postoperative intensive care unit (ICU) stay, open thoracotomy, operation time, intraoperative blood transfusion, and postoperative hospital stay were risk factors for postoperative complications. The neoadjuvant therapy group had a longer postoperative ICU stay (6.1% vs 12.4%; <i>P</i> = 0.036). However, postoperative morbidity did not differ significantly between the two groups (<i>P</i> = 0.134). The pathologic complete response rate for the patients receiving chemoimmunotherapy was significantly higher than for those receiving chemotherapy alone. Subgroup analyses indicated that only neoadjuvant chemoimmunotherapy significantly improved overall survival (hazard ratio [HR], 0.34; range, 0.14–0.85; <i>P</i> = 0.020).</p> Conclusion <p>The study confirmed that neoadjuvant therapy was safe and effective for patients with pneumonectomy, and that neoadjuvant chemoimmunotherapy had a favorable impact on patient prognosis.</p>