Abstract: Objective To analyze the clinical value of nerve block anesthesia combined with esketamine in open reduction and internal fixation of clavicle fractures. Methods A total of 99 patients with clavicle fractures who underwent open reduction and internal fixation at Sanshui Hospital, Foshan Hospital of Traditional Chinese Medicine from February 2023 to February 2024 were selected as study subjects. They were divided into three groups using a random number table: Group A (n= 32, receiving nerve block anesthesia alone), Group B (n= 33, receiving nerve block anesthesia combined with continuous intraoperative infusion of dexmedetomidine), and Group C (n=34, based on Group B with additional continuous intraoperative infusion of esketamine). Surgical and anesthesia-related indicators were recorded. Mean arterial pressure (MAP), heart rate (HR), and blood oxygen saturation (SpO₂) at baseline (T0), immediately after skin incision (T1), 30 min intraoperatively (T2), and at the end of surgery (T3) were compared. The patients were assessed using the Visual Analog Scale (VAS), the Richmond Agitation-Sedation Scale (RASS), and the Mini-Mental State Examination (MMSE). Adverse reactions were also monitored. Results Compared with Groups A and B, Group C demonstrated a significant reduction in anesthetic dosage and frequency of patientcontrolled analgesia pump activation, alongside a shorter onset of anesthesia and earlier recovery time (P ＜ 0.05). Group C exhibited higher SpO₂ at T2 than both Groups A and B, and higher SpO₂ at T1 and T3 compared with Group A (P ＜ 0.05). VAS scores at 6, 12, and 24 hours postoperatively were significantly lower in Group C than in Groups A and B (P ＜ 0.05). RASS scores at T1, T2, and 1 minute after awakening were significantly higher in Group C than in Groups A and B (P ＜ 0.05). Similarly, MMSE scores on postoperative day 1 and day 3 were significantly higher in Group C than in Groups A and B (P ＜ 0.05). No statistically significant difference was observed in the incidence of adverse reactions among the three groups (P ＞ 0.05). Conclusion Nerve block anesthesia combined with esketamine in open reduction and internal fixation for clavicle fractures can stabilize intraoperative hemodynamic parameters, improve sedative and analgesic effects, reduce postoperative cognitive impairment, and promote postoperative recovery.