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Background: The long-term success of root canal therapy depends on the effective debridement and removal of smear layer and debris from the canal. Root canals with difficult anatomy and complex systems pose great challenge to achieve this. Mechanical therapy alone cannot achieve this goal, various intracanal chemicals also have their own limitations along with the difficulty in reaching the farfetched and difficult areas, and hence, introduction of ultrasonic bypass system has been a boon for the endodontic therapy. Objectives: The aim of this study is to compare the various root canal medicaments along with ultrasonic bypass system in effectively cleaning the debris and smear layer from the various parts of the root canal system. Materials and Methods: Forty single-rooted anterior maxillary and mandibular human teeth were collected for this study, after disinfection, they were sectioned into three equal parts coronal, middle, and apical and these parts were later studies under SEM (Scanning Electron Microscope) and scoring as per the scoring criteria set before the study was done and results were then compared statistically. Results: Group with both ethylenediaminetetraacetic acid (EDTA) and NaOCl with ultrasonic bypass system was the most effective one, when compared with sterile water, NaOCl + ultrasonic bypass system, EDTA + ultrasonic bypass system. NaOCl + ultrasonic bypass system was more effective as compared with the EDTA + ultrasonic bypass system. Conclusion: Ultrasonic bypass system is a useful tool for debris and smear layer removal from a root canal system, but its effectiveness increases when both EDTA and NaOCl are used along with it. [ABSTRACT FROM AUTHOR]