Introduction: Failure of molar anesthesia is commonly encountered in our clinical practice ranging around 15% in normal pulps and 44%–81% in inflamed pulps. Effective pain management is challenging in such situations. The aim of the present systematic review was to enlist the reasons for local anesthesia failure in mandibular molars during root canal treatment and to assess the effectiveness of supplementary methods along with the conventional inferior alveolar nerve block (IANB) in achieving profound anesthesia. Materials and Methods: A literature search on Pubmed and Google scholar database from the year 1990–2020 was conducted using the keywords: “Molar anesthesia,” “Local anesthesia failure,” “Hot tooth,” “irreversible pulpitis.” The articles pertaining to the failure of IANB during endodontic treatment of mandibular molars and the techniques for the improved success of molar anesthesia were reviewed. The data were analyzed in terms of author, year, type of study design, study population and type of intervention, method of assessment of outcome, outcome assessed, result and clinical recommendations. Results: The search yielded 9090 articles, from which the specific articles relevant to the topic were reviewed. The articles were reviewed independently by two authors. Finally, a total of 7 randomized controlled trials fulfilling the eligibility criteria were analyzed and subjected to qualitative assessment. Conclusion: The failure of IANB could be attributed to several reasons such as anatomical variations, Operator Technique, Presence of inflammation, and Psychological reasons. In addition, there is a positive association in using adjuncts for achieving effective anesthesia in mandibular molars.