Polymethyl methacrylate (PMMA) is widely used as a denture base material due to its ease of processing, aesthetics, and biocompatibility. However, PMMA possess inferior mechanical strength. Alumina nanoparticle reinforcement was experimented to enhance the mechanical and physical properties of PMMA. This systematic review and meta-analysis evaluated the effect of alumina reinforcement on PMMA denture base materials. A systematic search was conducted in PubMed, Cochrane Library, Trip, and Google Scholar databases for studies published until December 31, 2024. In vitro studies assessing PMMA reinforced with alumina nanoparticles and reporting measurable mechanical properties were included. The modified CONSORT checklist for in vitro studies was applied for quality assessment, and a meta-analysis was performed to evaluate the effect of alumina reinforcement on flexural strength, with heterogeneity measured using I² statistics. Eleven in vitro studies met the inclusion criteria. Alumina nanoparticles significantly improved flexural strength, impact resistance, and surface hardness; however, excessive concentrations led to agglomeration, negatively affecting mechanical properties. The meta-analysis showed a significant increase in flexural strength (SMD = 3.33, 95% CI: 0.85-5.81, p = 0.009), though high heterogeneity (I² = 94%) indicated substantial variability among studies. Alumina nanoparticles improve PMMA’s mechanical properties, but variability in studies requires standardized protocol and further clinical research.