Root canal failure and secondary endodontic infection are frequent clinical scenarios in dentistry. The main microorganisms implicated in root canal therapy failure are persistent Enterococcus faecalis, Candida albicans, and Staphylococcus aureus. To combat the impact of disease resistance, scientists are concentrating on alternative antimicrobial root canal sealers. Nanomaterials are a recent development in endodontic materials that exhibit great antimicrobial properties, making them an ideal material choice for root canal sealers. This systematic review aims to compare the antimicrobial properties of conventional root canal sealers to those incorporating green synthesized nanoparticles between 2010 and 2024. A well-constructed protocol was established and registered with PROSPERO (CRD42021286373). Ethics approval was obtained from the Biomedical Research and Ethics Committee from the University of the Western Cape (UWC; BM22/1/4). PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) reporting guidelines were followed. The included criteria demonstrate the green synthesized nanoparticles studies where the nanoparticles (NPs) are incorporated in root canal sealers. MeSH (Medical Subject Headings) terms were used for the search strategy of the systematic electronic databases for articles published in English between 2010 and 2024. The selected databases included Scopus, PubMed, Web of Science, Science Direct, EBSCOhost, SpringerLink, and Wiley Online. A quality assessment tool for laboratory studies will be used to critically appraise the included studies. If applicable, statistical measures (mean, SD, etc) will be used for data analysis and presentation of the results. The protocol is registered with PROSPERO. A preliminary search was conducted using a determined search strategy across 8 electronic databases, and the review is now complete. It is anticipated that the results of this systematic review may reveal the increased interest and application for nanoparticle-enhanced root canal sealers. This will aid in the future development of root canal sealants and mitigate the risk of endodontic failure. PROSPERO CRD42021286373; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=286373. DERR1-10.2196/51351.