Background: The advent of immunotherapy has significantly improved survival outcomes in advanced non-small cell lung cancer (NSCLC). In this evolving context, salvage surgery has emerged as a potential curative strategy, despite the risk of serious complications. This study aimed to evaluate the safety and efficacy of surgical resection following chemo-immunotherapy in patients with initially unresectable NSCLC. Methods: We retrospectively analyzed patients with stage III–IVB NSCLC who underwent salvage surgery at our institution between January 2019 and June 2024. All cases were initially deemed unresectable by a multidisciplinary tumor board. Perioperative complications, complete (R0) resection rate, major pathologic response (MPR), complete pathologic response (pCR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Twenty-one patients (thirteen males, eight females; median age: 68 years [IQR: 9]) were included. Reasons for initial unresectability were metastatic disease (28.6%), N2 bulky disease (14.3%), local invasiveness (33.3%), or a combination of factors (23.7%). Chemo-immunotherapy was administered in 19 patients (90.5%), while 2 (9.5%) received immunotherapy alone, with a median of four treatment cycles (IQR: 1). Complete (R0) resection was achieved in all patients (100%). Anatomical resections were performed in 17 patients (81%), predominantly lobectomies (66.7%). There were no intraoperative or major postoperative complications, and 30-day mortality was zero. Median hospital stay was 7 days (IQR: 4). pCR and MPR were achieved in 33.3% and 14.3% of patients, respectively. After a median follow-up of 17 months (IQR: 19), the estimated 3-year PFS and OS were 50.9% and 66.3%, respectively. Recurrences included locoregional (4.8%), distant (14.3%), and combined (14.3%). Cox regression analysis identified stage III at diagnosis (OR: 0.292; 95% CI: 0.093–0.912; p = 0.034) and achieved pCR or MPR (OR: 0.113; 95% CI: 0.013–0.959; p = 0.046) as independent predictors of improved PFS. Conclusions: Salvage surgery after chemo-immunotherapy in initially unresectable NSCLC appears to be a safe and effective strategy in selected patients, offering favorable pathological responses and encouraging mid-term oncologic outcomes.