Background: Percutaneous vertebroplasty is a minimally invasive procedure, usually performed under local anesthesia with either general anesthesia or conscious sedation. In this study, we compared the efficacy and safety of propofol versus the combined use of meperidine and midazolam for conscious sedation in percutaneous vertebroplasty. Methods: This prospective randomized study was conducted within 6 months on sixty patients undergoing percutaneous vertebroplasty. The patients were divided into two equal groups: Group I received propofol, while Group II received meperidine and midazolam. The time required to achieve sufficient sedation, emergence time, recovery time, hemodynamic monitoring throughout the procedure, patient's and surgeon's satisfaction, and incidence of postprocedural complications were all recorded. Bispectral index and end-tidal carbon dioxide measurement were used to assess sedation level and to ensure patient safety throughout the procedure. Results: Demographic data from both groups were comparable. The time taken to reach sufficient sedation, emergence time, and recovery time were shorter in Group I than that in Group II (P = 0.001). Patients in both groups were hemodynamically stable throughout the procedure. Surgeon's satisfaction was higher in Group I (96%) than that in Group II (80%), while patient's satisfaction was nearly equal in both groups, without significant postoperative complications. Conclusions: Propofol was superior to the combined use of midazolam and meperidine for conscious sedation in percutaneous vertebroplasty. It helped in achieving a moderate sedation level in less time and offered rapid emergence from sedation, with shorter recovery time.