Reducing postoperative pain enhances the ability to breathe deeply and cough effectively, thereby protecting cardio pulmonary functions. This leads to better oxygenation and probable preservation of positive myocardial oxygen balance, which in turn reduces hospital stay and cost and increases patient satisfaction Aims: This study compared the clinical effects and recovery characteristics of ketamine versus fentanyl when used as an adjuvant along with dexmedetomidine infusion intraoperatively. Methods: randomized prospective clinical study in which total of 60 patients of age 18-60 years undergoing major surgeries were divided into two groups: Group (D + K) received an intraoperative infusion of ketamine 0.5 mg/kg/h, while group (D + F) received fentanyl 0.5 μg/kg/h along with intravenous dexmedetomidine 0.5 μg/kg/h. Intraoperative heart rate (HR), mean blood pressure, and oxygen saturation were recorded at 0 min, 10 min of induction, and thereafter every 30 min throughout the procedure. Ramsay sedation score (RSS) and visual analogue scale (VAS) score were measured at the end of the surgery, at 2 hours, 4 hours, and 6 hours. Results: Decreased in HR and mean blood pressure was more with a tendency of developing hypotension in the fentanyl group compared to the ketamine group. Post-anaesthesia care unit (PACU) stay, need for muscle relaxant and VAS score for pain were also significantly lesser in the ketamine group. Conclusion: Dexmedetomidine with ketamine provided better haemodynamic stability and reduced PACU stay compared to dexmedetomidine with fentanyl.