Background: Post-operative delirium in elderly patient needed to operative procedures is a risk factor to deteriorate outcomes of this patient. The prevalence of post-operative delirium ranges from 10% to 37% in elderly patient undergoing anesthesia especially in those receiving general anesthesia and is related to poor function recovery, increasing length of stay in hospital, increasing the frequency of early post-operative cognitive dysfunction (POCD) and morbidity. Objective: to compare the efficacy of dexmedetomidine, propofol, and ketamine in elderly patients undergoing spinal anesthesia for prevention of post-operative delirium. Patients and Methods: A prospective, randomized controlled study was conducted on 60 patients of both genders, aged 60 -75 years, with ASA physical status I, II and III, scheduled for elective surgery in the lower abdomen and lower limb undergoing spinal anesthesia from March 2019 to March 2020 at Al-Azhar University Hospital (Damietta). They were randomized into three equal groups: Group I received premedication dexmedetomidine (1 μg/kg), given slowly intravenously over 10 minutes, Group II received intravenous propofol (0.5 mg/kg), and Group III received intravenous ketamine (0.5 mg./kg). The primary endpoint was the incidence of post-operative delirium (POD), which was assessed using confusion assessment method (CAM) from the first postoperative day to the third postoperative day. Results: Dexmedetomidine group has a lower incidence of postoperative delirium than propofol group without statistical significant difference, while ketamine group has high incidence of postoperative delirium with statistical significant difference than other two groups numbering from statistics. Conclusion: Dexmedetomidine group was associated with a lower incidence of POD than propofol group, while ketamine group was associated with a high incidence of POD than other two groups and thus resulting in better short recovery, short hospital stay, and thus decreasing health care cost and morbidity.