Introduction Endoscopic retrograde cholangiopancreatography (ERCP) is vital for diagnosing and treating biliary and pancreatic diseases, necessitating deep sedation typically achieved through total intravenous anesthesia. Propofol, with its favorable pharmacokinetic profile, is the preferred sedative, but conventional administration methods of mg/kg boluses or infusion rates pose challenges. Target-controlled infusion (TCI) systems offer a solution that ensures precise dose delivery of propofol. Despite its widespread use, the literature lacks specific guidance on the target plasma concentration (Cp) of propofol for sedation in patients undergoing ERCP. Methods A prospective interventional study was conducted at the Institute of Liver and Biliary Sciences, Delhi, India to determine the target Cp of propofol for sedation during ERCP. The study enrolled 86 American Society of Anesthesiologists (ASA) grade I and II patients aged 18-70 years. The primary objective was to establish the optimal propofol concentration for sedation as guided by a bispectral index (BIS) value of 60-70. Secondary outcomes included induction time, recovery time, total propofol consumption, and the occurrence of adverse events (if any). The Marsh pharmacokinetic model guided the TCI pump, adjusting Cp until the target sedation was achieved. Results The mean Cp of propofol to maintain the BIS value 60-70 was 2.21 ± 0.42 µg/ml. Age-wise analysis revealed variations, emphasizing the need for individualized dosing. Induction time was 4.21 ± 0.68 minutes; recovery times were seven minutes (median, IQR: 5-10 minutes) for BIS >80 and seven minutes (median, IQR: 5-10 minutes) for achieving a Modified Observer's Assessment of Alertness/Sedation score of ≥5. The mean propofol consumption was 6.24 mg/kg/hr. Side effects were minimal, with 1.16% experiencing transient hypoxia and hypotension. Conclusion The study establishes a mean target propofol concentration of 2.21 ± 0.42 µg/ml for sedation in ASA I and II patients undergoing ERCP.