In general, endodontic infections are polymicrobial infections, and the severity of the infection depends on the pathogenicity of the microbes and the resistance of the host. For the treatment of endodontic infections, antibiotics are widely used; however, the development of resistance raises concerns for their wide-scale application; hence, there is always an unmet need to develop alternative treatment strategies in the fight against endodontic infection. Basically, the searches were conducted in PubMed (459), Science Direct (559 articles), and WOS (493) using keywords and phrases to identify relevant articles. Search criteria consisted of combinations of the following words and phrases: Bioactive peptides, endodontic infections, oral microbiota, intraradicular infections, extraradicular infections, In vitro, In vivo study, clinical trials, mechanism of peptides, oral biofilm. It is important to note that bioactive peptides are short sequences of 2-40 amino acids, displaying various functional and structural diversities, and exhibiting a wide range of therapeutic activity. This comprehensive review discusses various aspects related to bioactive peptide sources; chemistry; biosynthesis; bioavailability; safety along with the periradicular disease, oral microbiota, and microbial analysis; molecular mechanisms of pathogenicity; host susceptibility; prediction markers; focal infection; and bioactive peptide resistance as well as approaches to overcome peptide resistance. Overall, this review will enlighten the readers with the prospective potential of bioactive peptides against endodontic infections.