Poly(methyl methacrylate) (PMMA) materials are highly susceptible to microbial colonization, predisposing patients to oral infections. To address this concern, we loaded PMMA samples with montmorillonite clay (MMT), a crystalline nanoparticle, in combination with chlorhexidine (CHX) or metronidazole (MET) targeting improved antimicrobial action. PMMA samples were prepared with or without MMT loaded with either CHX or MET, establishing the following groups: control (acrylic resin without the addition of nanoparticles), MMT/CHX (acrylic resin with 5% by weight of MMT loaded with CHX), and MMT/MET (acrylic resin with 5% by weight of MMT loaded with MET). Mechanical properties such flexural strength, flexural modulus, and Knoop hardness were evaluated using a universal testing machine. Antimicrobial efficacy was assessed via agar diffusion tests against Enterococcus faecalis and Porphyromonas gingivalis. The addition of MMT loaded with CHX did not affect the flexural strength and flexural modulus of PMMA compared to the control group (p > 0.05). However, MMT/MET reduced all mechanical properties of PMMA (p < 0.05). Both loaded-PMMA materials demonstrated antibacterial activity against E. faecalis but not against P. gingivalis. In conclusion, the incorporation of MMT/CHX into acrylic resin appears to be the most promising approach to combat microbial colonization while preserving PMMA mechanical properties. Future research should focus on optimizing material characteristics to enhance antimicrobial properties, paving the way for clinical applicability.