During endodontic treatment, eliminating microorganisms from the root canals should be considered with utmost importance. Before filling the canal, every effort should be made to ensure optimal shaping and adequate disinfection of the root canal system. This systematic review aimed to compare the efficacy of herbal agents with sodium hypochlorite (NaOCl) in reducing the microbial load while used as a root canal irrigant. The research question in the present study was to assess “Is there a significant difference in reducing microbial load comparing sodium hypochlorite (NaOCl) and herbal agents.” Electronic databases (PubMed, Scopus, and Web of Science) were searched from their start dates to November 2020 using strict inclusion and exclusion criteria and reviewed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Only in vitro studies comparing herbal agents with NaOCl regarding antimicrobial efficiency were included. Two reviewers independently assessed the included article. 825 articles were obtained from an electronic database. Twenty papers were included for review of the full text. Eleven papers were excluded because they did not meet the inclusion criteria. Finally, nine articles were included in the systematic review. The present systematic review was at the in vitro level; therefore, the result cannot translate the exact clinical conditions. This systematic review concludes that herbal agents cannot be used as a main irrigant for canal disinfection.