Neoadjuvant therapy improves survival benefits in patients with locally advanced non-small cell lung cancer but increases tissue density, presenting challenges for surgeons. To compare the differences in surgical complexity and short-term prognostic outcomes between neoadjuvant targeted therapy (NTT) and neoadjuvant chemoimmunotherapy (NCI). This study enrolled 106 patients underwent curative surgery after neoadjuvant therapy between January 2020 and December 2023 at the National Cancer Center of China. Differences in surgical complexity and short-term prognostic outcomes between the two neoadjuvant therapy cohorts were evaluated. The pathological indicators such as pathological response rate and lymph node upstaging/downstaging were then analyzed. In total, 33 patients underwent NTT and 73 underwent NCI preoperatively. Patients who received NTT showed a higher minimally invasive surgery rate (84.8% versus 53.4%, p < 0.01), shorter operative time (144 versus 184 min, p < 0.01), lower conversion rate (3.3% versus 17.8%, p = 0.03), less postoperative drainage (day 3: 140 versus 200 mL, p = 0.03), and lower incidence of postoperative complications including arrhythmias (6.1% versus 26%, p = 0.02). The pathological response rate in the NTT and NCI groups was 70% and 75%, respectively, with the latter group showing a higher complete pathological response rate. The two groups had no significant differences in major pathological response and lymph node pathological response rate. Patients who received NTT presented fewer surgical challenges for surgeons and had better surgical outcomes than those who received NCI therapy, with comparable pathological response rates between the two cohorts. Accordingly, NTT is the preferred induction regimen for patients harboring mutation status.