Background: Upper gastrointestinal endoscopy (UGE) often requires sedation to ensure patient comfort and procedural success. This study aimed to compare the effects of nebulized dexmedetomidine and ketamine, as adjuvants to propofol, on hemodynamics, sedation quality, and perioperative outcomes during UGE. Methods: In this randomized controlled trial, 111 adult patients scheduled for UGE were assigned to receive nebulized dexmedetomidine (Group D)(n=37), ketamine (Group K)(n=37), or saline (Group C) (n=37), followed by propofol sedation. Repeated measurements of heart rate (HR), mean arterial pressure (MABP), respiratory rate (RR), and sedation scores were recorded. Propofol requirements, recovery time, agitation, and complications were also noted. Results: Group D showed significantly lower HR, MABP, and RR compared to Groups K and C at all time points after drug administration (p<0.05). Sedation scores were significantly lower in Group D compared to Groups K and C across all intervals (p<0.05). Group D also required less propofol (1.13±0.65 mg/kg) than Group K (2.24±0.57 mg/kg) and Group C (2.8±0.54 mg/kg), and had a shorter recovery time (6.41±2.9 min) than both Group K (10.72±2.4 min) and Group C (12.4±1.74 min) (p<0.05 for all). Group D experienced the least percentage of severe emerging agitation (5.4%) and Group C the most (74.3%) (p<0.001).For sore throat and respiratory depression, there were no statistically significant differences between groups. Conclusion: Compared to nebulized ketamine or saline, nebulized dexmedetomidine, when used as an adjuvant to propofol, offers improved sedation, better hemodynamic stability, and a faster recovery with less emerging agitation during UGE without increasing side effects.