An infectious environment is reported to hinder the process of pulp tissue regeneration by damaging the cells responsible for tissue formation, including stem cells in the periapical tissues. Therefore, a sterile environment is critical for pulp tissue regeneration, which can be achieved by copious irrigation and intracanal medicament (ICM) placement. This systematic review compares the effect of calcium hydroxide (Ca(OH)) and various antibiotic pastes, such as triple antibiotic paste (TAP), modified triple antibiotic paste (MTAP), and double antibiotic paste (DAP),on dentin microhardness when used as ICMs. MeSH terms and specific keywords were used to search Scopus, EBSCOhost, Cochrane Library, and PubMed. In vitro studies that compared the impact of Ca(OH) and antibiotic pastes, such as TAP, MTAP, and DAP,on dentin microhardness were included. Data from the included articles were extracted, and their quality was assessed using the revised Quality Assessment Tool for In Vitro Studies (QUIN) tool. Seven articles were included for the qualitative synthesis, and data were extracted from each. Within the scope of this systematic review, Ca(OH), an alternative ICM recommended by the American Association of EndodonticsGlossary of Endodontic Terms for REPs, showed a lesser reduction in microhardness than TAP. DAP and MTAP caused a reduction in dentin microhardness compared to that of Ca(OH).