Colonoscopy is a key procedure for the early detection of colorectal cancer. Despite its importance, the discomfort associated with colonoscopy often requires sedation, and the ideal sedation regimen remains to be determined. In this prospective randomized controlled trial, patients scheduled for colonoscopy were randomly assigned to two different sedation protocols. Group A received a combination of midazolam and propofol, while group B was given midazolam and pethidine. The study analyzed data from 51 patients, with 23 in group A and 28 in group B. The incidence of adverse events was similar across both groups. Additionally, no significant differences were observed in cecal intubation times or total procedure durations. Notably, group A had a lower frequency of required postural changes (1.0±0.7 vs. 1.5±0.7, p=0.02) and a reduced rate of manual compression (52.2% vs. 82.1%, p=0.02). There were no significant differences between the groups regarding subjective pain or overall satisfaction. Both sedation regimens were found to be safe and effective. The midazolam and propofol combination was associated with a smoother procedure, evidenced by fewer postural adjustments and less manual compression needed during colonoscopy.