Objective To explore the use of oxycodone combined with remifentanil for postoperative analgesia in the elderly patients with laparoscopic radical resection of colorectal cancer. Methods A total of 140 elderly patients were selected as the research subjects, who underwent selective laparoscopic radical resection of colorectal cancer under general anesthesia in the Second Affiliated Hospital of Hainan Medical University from May 2021 to May 2023. They were divided into an observation group and a control group by the random number table method, with 70 patients in each group. The control group was given patient-controlled analgesia (PCA) pump for analgesia after surgery, loaded with 0.2 μg/ml of remifentanil. On the basis of the control group, the observation group was given intravenous injection of 0.1 mg/kg of oxycodone hydrochloride prior to the completion of the surgery, and postoperative PCA was loaded with 0.2 μg/ml of remifentanil + 0.3 mg/ml of oxycodone hydrochloride. The two groups were compared in postoperative pain, PCA use and remedial analgesia, pain mediators and adverse reactions. SPSS 22.0 was used for statistical analysis. Data comparison between two groups was performed using t test orχ² test depending on data type. Results The Visual Analogue Scale (VAS) scores of pain at rest and during activity were lower in the observation group than those in the control group at 2,6, 12,24 and 48 hours after surgery (P<0.05). The observation group had longer PCA time and fewer effective compressions than the control group from the completion of surgery to the first compression (P<0.05). Serum levels of substance P and prostaglandin E2 (PGE2) in both groups at 24 hours after surgery were higher than those before surgery (P<0.05), but those in the observation group were lower than those in the control group (P<0.05). The incidence of nausea and vomiting in the observation group was lower than that in the control group (P<0.05). Conclusion Oxycodone combined with remifentanil can enhance the postoperative analgesic effect, reduce the use of analgesics, and reduce the incidence of postoperative nausea and vomiting in the elderly patients with laparoscopic radical resection of colorectal cancer.