Abstract Background: Aim of the Work To evaluate the efficacy of melatonin versus mirtazapine administration in preventing emerging agitations in adults following nose surgery. Patients and Methods This prospective randomized clinical trial study was conducted at Ain Shams University Hospitals, Cairo, Egypt. One hundred and sixty five (165) consecutive patients scheduled for elective nasal surgery under general anesthesia where nasal packing was packed in both sides. The patients' age was above 21 years old from both genders and with the American Society of Anesthesiologists physical status classification (ASA) I or II. Results The mirtazapine category had the greatest patients` satisfactions scores 24 hours after surgery, followed by the melatonin category, while the control group had the lowest score. There were statistically significant differences between the control group and other categories, but not between the mirtazapine and melatonin groupings. Conclusion Prophylactic administration of melatonin or mirtazapine attenuated emergence agitation with minimal hazards in patients scheduled for nasal surgery under general anesthesia with priority to mirtazapine.