Objective To study the analgesic effects of different perioperative analgesic regimens in patients underwent thoracoscopic lobectomy. Methods 120 patients who underwent pulmonary wedge resection in Xuzhou Central Hospital from Oct 2021 to Jun 2023 were enrolled and divided into 4 groups by random digital table method. The four groups were given general anesthesia, group A was given intravenous controlled analgesia by sufentanil (PCIA) , and group B was given chest wall + intercostal nerve block combined with intravenous controlled analgesia by sufentanil (PCIA), and group C was given intravenous controlled analgesia by esketamine (PCIA), and group D was given chest wall + intercostal nerve block combined with intravenous controlled analgesia by esketamine (PCIA). The general data and visual analogue scores (VAS) after 2h, 6h, 24h, 48h and 72h of operation were compared among the four groups. Before analgesia and after 48h of operation, the levels of pain mediators [including serum neuropeptide Y (NPY) and substance P (SP) ] and the incidences of adverse reactions were compared among the four groups. Results There were no significant differences in the general data among the four groups (P 0.05). The differences in VAS scores were statistically significant differences by repeated measurement analysis of variance (P 0.05). The VAS scores in the four groups after 6h and 24h of operation were higher than those after 2h of operation, which after 72h of operation were lower than those after 24h of operation, and those after 48h and 72h of operation were lower than those after 6h and 24h of operation, and the scores after 72h of operation were lower than those after 48h operation. Compared among the four groups, the VAS scores in group D were lower than the other three groups, which in group B were lower than those in group A and C, which in group C were lower than those in group A, with statistically significant differences (P 0.05). The NPY, and SP levels in the four groups after 48h of operation were higher than those before analgesia, and there were no significant differences in the levels of pain mediators among the four groups before analgesia (P 0.05). The NPY, and SP levels in group D after 48h of operation were lower than those in the other three groups (P 0.05), which in group B were lower than those in group A and C (P 0.05), and the levels in group C were lower than those in the group A(P 0.05). There was no significant difference in the adverse reactions among the four groups (P 0.05). Conclusion chest wall + intercostal nerve block combined with intravenous controlled analgesia by esketamine has better analgesic effect on pulomonary wedge resection, more effective effects on inhibit the expression of pain mediators.