<p>Neoadjuvant targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is emerging as a strategy to improve outcomes in resectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) with EGFR mutations. We conducted a systematic review of clinical trials and studies, following PRISMA guidelines, to evaluate the efficacy, safety, and surgical feasibility of neoadjuvant EGFR-TKI therapy in this setting. Literature was searched for studies reporting outcomes of neoadjuvant TKIs (e.g., gefitinib, erlotinib, afatinib, osimertinib) in resectable stage III NSCLC. Key endpoints included radiologic response rates, pathological response (pCR and major pathologic response, MPR), complete resection (R0) rates, surgical outcomes, and adverse events. A total of 15 studies (including one randomized trial and multiple phase II trials/cohorts) were analyzed, encompassing over 400 patients. Neoadjuvant EGFR-TKIs yielded high objective response rates (pooled ORR ~ 57%, up to 70–80% with third-generation TKIs). However, pathological complete response was rare (pooled pCR ~ 3%) and MPR rates remained modest (often &lt; 15%), underscoring a difference compared to neoadjuvant chemoimmunotherapy. Complete resection (R0) rates were excellent (approximately 90% in patients undergoing resection), and neoadjuvant TKIs enabled surgical downstaging in ~ 40–74% of cases. Treatment was well tolerated, with primarily grade 1–2 rash and diarrhea; severe adverse events ≥ grade 3 were under 10%. Importantly, surgery after TKI therapy was feasible, with no increase in perioperative morbidity reported. In some cases, tumor shrinkage allowed conversion of an initially unresectable or complex case to a less extensive resection (e.g., sleeve lobectomy instead of pneumonectomy). In comparison to historical neoadjuvant chemotherapy, EGFR-targeted therapy significantly improved radiologic response and progression-free survival, while avoiding the added toxicity of chemotherapy. Compared to neoadjuvant chemo-immunotherapy (which achieves higher pCR rates), targeted therapy is specific to oncogene-driven tumors and has shown efficacy in EGFR-mutant tumors where immunotherapy alone is often ineffective. This review highlights that neoadjuvant EGFR-TKI therapy is a safe and feasible approach that can increase resectability and preserve lung tissue in stage III EGFR-mutant NSCLC. The combination of novel targeted agents with advanced surgical techniques (including sleeve resections and robotic-assisted approaches) offers promising results. Nevertheless, due to the lack of significant pathological complete responses, adjuvant therapy and long-term outcomes remain concerns. Ongoing trials (e.g., NeoADAURA) will further clarify the role of EGFR-TKIs ± chemotherapy in the neoadjuvant setting. In conclusion, for resectable stage III EGFR-mutant NSCLC, neoadjuvant EGFR-targeted therapy achieves high response rates and surgical success with manageable toxicity. Multimodal therapy incorporating targeted agents and lung-sparing surgical strategies may improve patient outcomes. Future research should focus on optimizing combination regimens, identifying predictive molecular markers of response, and confirming survival benefits in this subset of lung cancer.</p>