Objective To compare the analgesic effect, duration and incidence of adverse reactions of liposome bupivacaine (LB) and bupivacaine hydrochloride after intercostal nerve block in single-port thoracoscopic lung surgery. Methods In Department of Thoracic Surgery of the First Affiliated Hospital of Xinxiang Medical University between September 2023 and March 2024, 228 patients who needed to undergo thoracoscopic lung surgery were selected and divided into two groups by random number table method: a group B with bupivacaine hydrochloride (n=118), and a group LB with LB (n=110). Intraoperative intercostal nerve block was performed under endoscopy, and the time of first use of analgesic drugs after surgery, cumulative use of opioids 72 h after surgery, incidence of postoperative nausea and vomiting, length of stay and other indicators were evaluated and recorded. Results Visual analogue scale (VAS) scores at 4 h, 8 h, 12 h, 24 h, 48 h and 72 h in the LB group were significantly lower than those in the group B (P<0.05). The total number of activities within 48 h after surgery in the group B was significantly lower than that in the LB group (P<0.05), and the postoperative hospitalization stay in the LB group was shorter than that in the group B, but the difference was not statistically significant. There was no statistical difference between the two groups in postoperative adverse reactions. Conclusion Intercostal nerve block with LB during single-port thoracoscopic lung surgery can significantly reduce postoperative pain, improve quality of life, and promote recovery of the patients. It is worthy of clinical application.