Background and Aim: Selecting the ideal drug combination for effective monitored anesthesia care to keep patients comfortable and safe during evacuation of chronic subdural hematoma is a challenge. Our hypothesis was that the combination of dexmedetomidine with ketamine might provide safer monitored anesthesia care keeping airway patency and stable hemodynamics in comparison to dexmedetomidine-propofol combination during burr-hole surgery for evacuating chronic subdural hematoma in high-risk patients. Methods: A total of 56 paticipants were allocated into two groups in this randomized prospective double-blind study by a computer-generated randomization table. DK group (n = 28): Patients were given a mix of ketamine (1 mg/kg) and dexmedetomidine (1 μg/kg) diluted in 10 ml of saline solution infused over 10 min as an intravenous bolus dose. This was followed by a continuous infusion of 0.5 μg/kg/h dexmedetomidine with 0.5 mg/kg/h ketamine. DP group (n = 28): Patients were given a mix of propofol (0.5 mg/kg) and dexmedetomidine (1 μg/kg) diluted in 10 ml of saline solution infused over 10 min as an intravenous bolus dose. This was followed by a continuous infusion of 0.5 μg/kg/h dexmedetomidine with 0.5 mg/kg/h propofol. The infused solutions were in two separate syringe pumps. The target was to achieve a modified Observer’s Assessment of Alertness and Sedation score (OAA/S) of 3, and the infusion was stopped by finishing the skin suture. Results: The onset of sedation using OAA/S was significantly longer in the DK group (413.21 ± 49.18 s.) compared to (297.21 ± 37.68 s.) in the DP group. The number of participants with an airway obstruction score of 1 and 2 was significantly higher in the DK group compared to the DP group; however, those with a score of 3 were significantly higher in the DP group. The total number of patients needing intraoperative fentanyl was comparable between groups. The number of patients who developed intraoperative hypotension, bradycardia, bradypnea, and hypoxemia was significantly higher in the DP group compared to the DK group (p < 0.05). There was an improvement in postoperative Markwalder’s Neurological Grading Scale (MNG) scores compared to preoperatively in both the DK and DP groups. The recovery time was significantly longer in the DK group (8.75 ± 1.17 min) compared to (5.73 ± 0.75 min) in the DP group, with comparable surgeon satisfaction. Conclusions: Combining dexmedetomidine with ketamine is safer than dexmedetomidine with propofol for effective monitored anesthesia care in high-risk patients undergoing burr-hole surgery for evacuating chronic subdural hematoma.