Abstract Background: Sedation during endoscopic procedures is essential for patient comfort and procedural success. This study aimed to compare the efficacy, safety, and recovery outcomes of three sedation combinations: ketamine + propofol (Group A), dexmedetomidine + propofol (Group B), and dexmedetomidine + ketamine (Group C) in patients undergoing endoscopic procedures. Materials and Methods: A prospective, randomized controlled trial was conducted involving patients scheduled for endoscopic procedures. Patients were divided into three groups based on the sedation regimen administered. Outcomes measured included sedation quality, hemodynamic stability, oxygen saturation, incidence of adverse effects, recovery time, and endoscopist satisfaction. Result: Group C (dexmedetomidine + ketamine) demonstrated a lower incidence of adverse effects, with 80% of patients experiencing no significant events such as falls in mean arterial pressure (MAP) or SpO2. The ketamine + propofol combination (Group A) required significantly more propofol rescue doses compared to the other groups. Dexmedetomidine- based combinations (Groups B and C) provided better sedation, stable hemodynamics, and fewer adverse events, while recovery times were longer than in the ketamine + propofol group (Group A). No significant differences were observed in endoscopist satisfaction across the groups. Conclusion: Dexmedetomidine-based sedation combinations, provide effective sedation with minimal adverse effects, maintaining stable hemodynamics and oxygen saturation. These combinations are particularly suitable for patients with underlying conditions such as hepatic disease, offering a safer alternative to ketamine + propofol.