Gutta Percha (GP) cones are made in an aseptic environment, a number of investigations have shown the presence of bacteria in recently opened boxes and this contamination rises with incorrect handling, storage and aerosol application. Numerous physicochemical techniques have been documented aiming to boost the antibacterial activity of GP cones while ensuring its obturation requirements. This systematic review aimed to critically evaluate the efficacy of antibacterial activity of GP modified with various antibacterial agents. The protocol for this systematic review has been registered with the PROSPERO International prospective register of systematic reviews, registry No. CRD42024573067. The search was carried out across reputable databases, including PubMed/Medline, Web of Science, Scopus and it was specifically designed to include articles published until March 2024. The search queries in the database were formulated with the basis of PICO questions in combination with various Boolean operators such as AND, OR. MeSH terms used for the search included GP, antibacterial agents, nanoparticles, root canal treatment, medicated GP. The extraction of the information was done by two independent authors. The evaluation of the methodological quality of the included studies was assessed using QUIN TOOL. This systematic review was reported following the Preferred Reporting Items for Systematic Reviews (PRISMA 2020) guidelines. Initial search yielded 51 studies from database search. Out of 51, 9 articles ultimately satisfied the requirements and were therefore discussed in the current systematic review. The included studies were assessed and data were extracted and tabulated. Based on the results of the current systematic review, modified GP with various antimicrobial agents showed significantly increased antibacterial effectiveness than standard GP.