Background: Nocturnal or postoperative dexmedetomidine has been shown to reduce the incidence of delirium in critically ill surgical patients without an increase in any complications. However, it is not clear whether dexmedetomidine has preventive effect against delirium in the patients with high risk of postoperative delirium (POD) since no previous studies have clearly emphasized high-risk surgical patients. Method: In this single-center, double-blind, randomized controlled trial, we randomize 114 high risk POD patients defined by developed predictive scores and admitted to surgical intensive care units (SICUs) into 2 groups: nocturnal dexmedetomidine (9 pm – 6 am) and placebo. The outcomes were incidence of POD, delirium-free days, secondary delirium-related complications and concerned complications including hypotension and bradycardia. Other treatments apart from intervention are standardized. Intention to treat analysis is used to analyze all data. Hypothesis: We hypothesize that nocturnal dexmedetomidine giving to high-risk POD patients admitted to SICUs postoperatively would (1) reduce incidence of POD (2) improve delirium-free days (3) reduce secondary delirium-related complications (4) show no difference in hypotension and bradycardia between groups. Ethics and dissemination: The trial receives ethic approval from Siriraj Institutional Review Board. We plan to disseminate the results in peer-reviewed critical care medicine or anesthesiology-related journals, conferences nationally and internationally. Trial registration: TCTR20210217001