Introduction: Thorough knowledge of root canal morphology and its anatomical variations is essential for successful endodontic therapy. Methods: This report presents 3 rare cases of unusual tooth morphology involving mandibular first molar with 4 roots and variable number of canals. Results: The use of DOM, proper radiographic interpretation and modified access opening in these cases greatly contributed toward making a confirmatory diagnosis and successful endodontic treatment of four-rooted mandibular first molars with variable canal anatomy. Conclusions: Root canal anatomy often presents challenging situations that requires diagnostic approaches, access modification, and clinical skills to perform a successful endodontic treatment.