Objective To evaluate the safety and efficacy of basic anesthesia combined with local anesthesia in the preoperative localization of multiple pulmonary nodules. Methods The clinical data of 200 patients who underwent preoperative localization for multiple pulmonary nodules resection under single-port thoracoscopy in Nanjing Brain Hospital from July 2023 to September 2023 were extracted. They were divided into a group A and a group B, according to the localization method. The group A consisted of 100 patients who were localized under local anesthesia, and the group B consisted of 100 patients who were localized with basic anesthesia combined with local anesthesia. The basic clinical characteristics, localization success rate, incidence of localization complications, localization time, and pain score of the two groups were compared and analyzed. Results The incidence of localization complications (4% vs. 13%), localization time [(19.9±8.66) min vs. (15.23± 5.98) min], and pain score (2.01±2.09 vs. 3.29± 2.54, P≤0.05) in the group B were significantly lower than those in the group A, and the differences were statistically significant. The localization success rate of the group B was significantly higher than that of the group A (98% vs. 92%, P≤0.05), and the difference was statistically significant. Conclusion Basic anesthesia combined with local anesthesia for preoperative localization of multiple pulmonary nodules under mobile CT has the advantages of short localization time, fewer localization complications, high safety, high success rate, and high patient comfort, and has certain clinical promotion value.