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Purpose: This study aimed to evaluate the biological and mechanical properties of the poly(methyl methacrylate) (PMMA) denture base material as a vehicle incorporating novel hydroxyapatite nanoparticles (HA-NP) loaded with metronidazole (MZ) drug. Methods: HA-NP was prepared via wet-chemical-method, characterized by XRD, SEM/EDX, TEM, Fourier-transform infrared spectroscopy (FTIR), as well as the measurement of surface area and pore-size distribution. Four drug delivery formulas were prepared in the form of discs (10 x 2 mm) as follows: F1 (MZ/ HA-NP/PMMA), F2 (HA-NP/ PMMA), F3 (control-PMMA) and F4 (MZ/PMMA). Characterization of all formulas was performed using differential scanning calorimetry (DSC) and FTIR. MZ release rate, antimicrobial properties against three oral pathogens, cytotoxicity (MTT assay) and surface micro-hardness were also assessed. Statistical analysis of data was performed using one-way ANOVA test ( P < 0.05). Results: DSC thermograms showed compatibility among MZ, HA-NP and PMMA along with physical stability over 6 months storage period at room temperature. FTIR spectroscopy proved the absence of any possible chemical interaction with MZ. MZ-HA-NP/PMMA formula showed relatively better drug release compared to MZ-PMMA. Both formulas showed statistically significant antimicrobial potentials against two microbial strains. MTT demonstrated reduction in cell cytotoxicity after 96 hours with the least value for HA-NP. Surface micro-hardness revealed non-significant reduction compared with the control PMMA. Conclusion: A novel biocompatible drug nanocarrier (HA-NP) was developed and incorporated in PMMA denture base material as a vehicle to allow prolonged sustained drug release to manage oral infections., (© 2021 The Authors.)