INTRODUCTION: Postoperative delirium (POD) is a common complication, and it has a high incidence in neurosurgery patients. Awake craniotomy (AC) has been widely performed in patients with glioma in eloquent and motor areas. Most of the surgical procedure is frontotemporal craniotomy, and the operation duration has been getting longer. Patients undergoing AC are high-risk populations for POD. Dexmedetomidine (Dex) administration perioperatively might help to reduce the incidence of POD. The purpose of this study is to investigate the effect of Dex on POD in patients undergoing AC. METHODS: The study is a prospective, single-center, double-blinded, paralleled-group, randomized controlled trial. Patients undergoing elective AC will be randomly assigned to the Dex group and the control group. Ten minutes before urethral catheterization, patients in the Dex group will be administered with a continuous infusion at a rate of 0.2 µg/kg/h until the end of dural closure. In the control group, patients will receive an identical volume of normal saline in the same setting. The primary outcome will be the cumulative incidence and severity of POD. It will be performed by using the confusion assessment method in the first 5 consecutive days after surgery. Secondary outcomes include quality of intraoperative awareness, stimulus intensity of neurological examination, pain severity, quality of recovery and sleep, and safety outcomes. DISCUSSION: This study is to investigate whether the application of Dex could prevent POD in patients after undergoing AC and will provide strong evidence-based clinical practice on the impact of intraoperative interventions on preventing POD in AC patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05195034. Registered on January 18, 2022.