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Purpose: To compare the analgesic efficacy and safety of use of postoperative low-dose parenteral ketamine/midazolam combination, and postoperative parenteral dexmedetomidine in major non-cardiac surgeries. Methods: Major non-cardiac surgeries were performed in patients under propofol/morphine anesthesia. After the surgeries, patients received low-dose of ketamine with midazolam (KM cohort, n = 115), dexmedetomidine (DEX cohort, n = 112), or paracetamol infusion (PL cohort, n = 148). When visual analog scale score was > 4 in a resting condition, 3 mg bolus intravenous morphine was administered. Data for total morphine requirements and treatment-emergent adverse effects (within 2 days of postoperative treatment) were collected and analyzed. Results: Thirty-eight patients from KM cohort, 55 patients from DEX cohort, and 109 patients from PL cohort required 3 mg bolus intravenous morphine for postoperative pain management. Patients from KM cohort had nausea, vomiting, blurred vision, dizziness, and hallucinations, while patients in DEX cohort experienced headache and bradycardia post-surgery. Patients in PL cohort reported drossiness, constipation, urinary retention, and dry mouth. Conclusion: Postoperative low doses of ketamine + midazolam and dexmedetomidine are effective for postoperative pain management, and they produce low adverse effects. [ABSTRACT FROM AUTHOR]