AIM：To observe the efficacy and safety of flurbiprofen axidate in postoperative analgesia in patients with craniocerebral injury. METHODS: A total of 60 patients with acute craniocerebral injury admitted to the Department of Neurosurgery in our hospital from May 2021 to May 2023 were selected. They were randomly divided into flurbiprofen axetil group (flurbiprofen + fentanyl analgesia) and fentanyl group (fentanyl analgesia), and the CPOT score of analgesia target was ≤3 points. The onset time of analgesia, the dosage of fentanyl within 48 h, and the occurrence times of nausea and vomiting, upper gastrointestinal hemorrhage, bradycardia and hypotension during analgesia treatment were observed in the two groups. Serum CRP, IL-6, TNF-α, NSE and S100β protein levels were detected before and 24 h and 48 h after the operation. RESULTS: There were no significant differences in gender, age, BMI, admission GCS score between the two groups. When analgesia reached the target value of CPOT score ≤3 points, the time required for flurbiprofen ester group was shorter than that of fentanyl group (P<0.05), and the total amount of fentanyl used in flurbiprofen axetil group was lower than that of control group within 48 hours (P<0.05). There were no significant differences in postoperative nausea and vomiting, upper gastrointestinal hemorrhage, bradycardia and hypotension between the two groups (P>0.05). CRP, IL-6, TNF-α, NSE and S100β in flurbiprofen axetil group were significantly lower than those in fentanyl group at 24 h and 48 h after operation (P<0.05). CONCLUSION: Flurbiprofen exate can reduce the amount of analgesic fentanyl in patients with craniocerebral injury, and has anti-inflammatory effect to reduce brain injury, and can be effectively and safely used in the analgesic management of patients with craniocerebral injury.