Statement of problem: Denture base resins (DBRs), such as polymethyl methacrylate, are commonly used in the fabrication of removable dentures because of their physical, mechanical, and esthetic properties. However, the denture base acts as a substrate for microorganism adherence and biofilm formation, which may lead to denture stomatitis and be further complicated by fungal infections, of especial importance with geriatric and immunosuppressed patients. Therefore, methods to enhance the antimicrobial property of DBRs will be beneficial. Purpose: The purpose of this systematic review was to evaluate the literature on the antimicrobial activity of DBRs incorporating antimicrobial agents or materials. Material and methods: A search of English peer-reviewed literature up to February 2019 reporting on antimicrobial activity of DBRs with respect to antimicrobial agents or materials, antimicrobial test effects and methods, and conclusion or knowledge gaps was conducted by using Embase, Google Scholar, PubMed, and Web of Science databases. Search terms included denture base resin and antibacterial, denture base resin and antifungal, and denture base resin and antimicrobial. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied for subsequent data analysis. Results: Of 2536 identified articles, 28 met the inclusion criteria for the systematic review. Antimicrobial materials were divided into 3 groups: antimicrobial monomer or copolymer, phytochemical or phytomedical components, and other compounds. Strategies on how to incorporate these substances into DBRs and their impact on the reduction and prevention of the growth of microorganisms were identified. Conclusions: Although many efforts have been made to improve the antimicrobial ability of DBRs, this systematic review found that the effectiveness of incorporating of antimicrobial agents into DBRs has not been demonstrated conclusively.