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Knowledge about the influence of fillers in denture base resin is vague. This systematic review aimed to report the reinforcing effect of fillers on the mechanical properties of denture base resin by following PRISMA guidelines. Two electronic databases (Pubmed/Medline & Web of Science) were searched for articles using the keywords: fibers in denture base, fillers in denture base, and reinforcement of denture base. Laboratory studies complying with the inclusion criteria were reviewed according to the set protocol. The established focus question was: “Do reinforcing fillers positively influence the mechanical properties of polymethyl methacrylate (PMMA) heat polymerized denture base material?” A total of twenty-nine relevant papers qualified for final inclusion. Of these, 24 were determined to have a moderate risk of bias. Micron or nano-sized metal/metal oxides particles and glass fibers were the frequently used reinforcing agents. The trend of evaluating fractural strength (FS) was common. Most of the studies limited the use of reinforcing agents up to 5 wt.%. FS, fracture toughness (FT), and impact strength (IS) tend to increase if the fillers are chemically bonded and well-dispersed in denture base resin. Though fillers with a higher elastic modulus increase the hardness of the reinforced denture base resin, they compromise other mechanical properties. Well-dispersed lower filler loading PMMA denture base resin can enhance the FS, FT, and other related mechanical properties.