Background. Failure in the provision of inferior alveolar nerve block anesthesia (IANB) is a significant problem during endodontic treatment of irreversible pulpitis. Various methodologies have been advocated one of which is administration of premedication prior to anesthesia. Despite the considerable number of reports, the topic yet deserves more clarification. This systematic review was conducted to provide an oversight on the effectiveness of premedication prior to IANB in mandibular teeth. Methods. A PubMed and Cochrane Database search was conducted by using MeSH terms inferior alveolar nerve block + pulpitis and mandibular anesthesia+pulpitis. Two reviewers independently performed the screening, selection of papers, and data extraction. Papers in English language that included randomized clinical studies on the impact of different medications on the success of inferior alveolar block anesthesia in irreversible pulpitis were included. Additionally, relevant supporting literature was also used where necessary. Results. Initially, 118 papers were selected from PubMed and 68 were selected from Cochrane. Five additional articles were retrieved from Google Search. Following the elimination of duplicates and irrelevant articles, 35 studies were selected meeting the criteria. It was observed that there was moderate evidence to suggest that some premedications were partially effective for the enhancement of mandibular anesthetic effect in irreversible pulpitis. Conclusion. Though some medications appear to be promising, further supporting research will help highlight this significant topic which requires further clarification.