Background With the growing number of patients with coexisting pulmonary and mediastinal lesions detected, reports about simultaneous video-assisted thoracic surgery (VATS) for these concurrent diseases are still rare. To further explore the safety and effectiveness of simultaneous resection of pulmonary and mediastinal lesions by uniportal or biportal VATS, we retrospectively analyzed the clinical data of the largest series of cases to date. Methods From July 2018 to July 2021, all patients whose pulmonary lesions and mediastinal tumors were resected simultaneously in our institution were retrospectively reviewed. Their demographic and clinical data were collected and analyzed. Results A total of 54 patients were enrolled, of whom 44 underwent unilateral uniportal VATS, 3 underwent bilateral uniportal VATS and 7 underwent unilateral biportal VATS. Seven cases were converted to thoracotomy during surgery. For the remaining 47 patients with various demographic and clinical characteristics, most of the operations were completed within 3 h (n = 33, 70.2%) with blood loss of no more than 100 mL (n = 43, 91.5%). The duration of chest tube drainage was 5.66 +/- 3.34 days, and the average daily volume was 196.90 +/- 122.31 mL. Four cases of postoperative complications occurred during hospitalization. The length of postoperative hospital stay was 8.60 +/- 3.63 days. No severe complications or deaths were observed during follow-up. Conclusions Uniportal and biportal VATS are safe and effective for simultaneous resection of selected coexisting pulmonary and mediastinal lesions, but the indications and operational details need more evaluation.