AIM: To evaluate the effect of intravenous oxycodone administration at different timing on rebound pain following the resolution of intercostal nerve blockade after thoracoscopic surgery. METHODS: A total of 114 patients undergoing elective thoracoscopic surgery under general anesthesia between January and July 2024 were selected. The patients were aged 18 to 64 years, regardless of gender, with a BMI of 18 to 30 kg/m2, and classified as ASA I-II. The patients were randomly divided into three groups using a random number table: control group (Group C), oxycodone administration at the end of surgery group (Group Q1), and oxycodone administration 6 hours postoperatively group (Group Q2), with 38 patients in each group. Group C received a normal saline injection at the end of surgery, Group Q1 received an intravenous injection of oxycodone 0.04 mg/kg at the end of surgery, and Group Q2 received an intravenous injection of oxycodone 0.04 mg/kg at 6 hours postoperatively. Patients in the three groups were treated with a postoperative intravenous self-control analgesic pump (PCIA). The occurrence of rebound pain was recorded, the time of the first analgesic pump press, the number of presses, the dosage of sufentanil, and the need for rescue analgesia were also recorded. Numerical Rating Scale (NRS) scores at rest and during movement were recorded at 6, 8, 12, 24, 48 and 72 hours postoperatively. The Pittsburgh Sleep Quality Index (PSQI) was used to assess the sleep quality of patients the night before surgery and for two nights postoperatively. Adverse reactions such as respiratory depression, postoperative nausea and vomiting (PONV), and pruritus were recorded. RESULTS: Compared with group C and Q1, the incidence of rebound pain, postoperative sufentanil consumption, effective compression frequency of PCIA from 0-24 hours after surgery, and the rate of rescue analgesia were lower in Groups Q2 (P<0.05); Compared to Group C, the NRS scores at rest and during movement at 8, 12, and 24 hours postoperatively were significantly lower in Groups Q1 and Q2 (P<0.05). However, compared to Group Q1, Group Q2 exhibited lower NRS scores at rest and during movement at 8, 12, and 24 hours postoperatively (P<0.05). On the first postoperative night, the PSQI scores of patients in Group Q2 were significantly better than those in Groups C and Q1 (P<0.05). There was no statistically significant difference in the incidence of PONV among the three groups (P>0.05). No respiratory depression, drowsiness, or pruritus were observed postoperatively in any of the groups. CONCLUSION: Intravenous injection of 0.04 mg/kg oxycodone 6 hours after surgery can reduce the occurrence of rebound pain after intercostal nerve block resolution in thoracoscopic surgery and improves patients' sleep quality.