Objective: This study aims to compare the efficacy of propofol and midazolam in terms of adverse effect potentials and to determine the appropriate strategy for pediatric procedural sedation. Methods: A total of 200 pediatric patients (aged < 14 years) undergoing diagnostic procedures were recruited for this nonrandomized prospective controlled cohort study. The patients were assigned to 2 treatment arms: either propofol (Group 1: IV bolus dose of 2 mg/kg during a 2-minute period, IV maintenance dose of 100 mcg/kg/min) or midazolam (Group 2: IV bolus dose of 0.15 mg/kg during a period of 2 to 3 minutes) to achieve sedation. Demographic data, body weight, and clinical status of the patients were evaluated and recorded. The vital signs and sedation levels (ie, Ramsay sedation scale scores) were evaluated and recorded, as well as the complications detected and medications administered in 10-minute intervals throughout the sedation procedure. Findings between the study arms were compared. Results: Arterial blood pressures decreased significantly in both groups (P = 0.001). The patients in Group 1 experienced a greater difference in diastolic blood pressure (P = 0.001) than those in Group 2. Sedation scores in Group 1 were more favorable (P = 0.014) and reached the appropriate sedation level in a shorter time than those in Group 2 (P = 0.010). Likewise, recovery time of patients was shorter in Group 1 than in Group 2 (P = 0.010). Hypoxia was found to be more common in the propofol group, but the difference was not significant (P = 0.333). Conclusion: Propofol seems to be more effective, achieve the appropriate sedation level more quickly, and provide a faster onset of sedation than midazolam in pediatric procedural sedation and analgesia. Propofol is preferred for imaging studies (computed tomography and magnetic resonance imaging) to reduce the occurrence of undesired motion artefacts. Although both drugs are safe to use for sedation before pediatric imaging procedures, propofol is preferred with appropriate preparation.