Disinfection of the root canal system followed by abscess drainage or tooth extraction is generally sufficient to manage most chronic and even acute endodontic infections. Antibiotics in this circumstance are not needed. However, Gram-positive and Gram-negative facultative anaerobes involve a combination of polymicrobial infections and strictly anaerobic bacteria, such as odontogenic infections and particularly endodontic infections, can gain from antibiotics as an accessory to endodontic therapy. The Medline, Pubmed, Embase, NCBI, and Cochrane databases were searched for studies using systemic antibiotics to treat endodontic lesions. PubMed database was used for articles selection, and the following keys were used in the mesh ((“Antibiotics "[Mesh]) AND (“in endodontic management” [Mesh]) OR (Antibiotics in endodontic management) Mesh])). The focus was awarded to those studies which reported the diagnosis of endodontic disease therapy options and outcomes and data on the type of antibiotic prescribed. It is imperative to improve upon current antibiotic-prescribing manners in the therapy of endodontic infections and to introduce educational initiatives to inspire their comprehensible and appropriate use, as antibiotics tend to be over-prescribed for endodontic infection management.