This study is aimed at evaluating the hybrid reinforcement effects of zirconium oxide nanoparticles (nano-ZrO2) and glass fibers (GFs) at different ratios on the flexural and impact strengths of a polymethylmethacrylate (PMMA) denture base. A total of 160 specimens were fabricated from heat-polymerized acrylic resins using the water bath technique. For the control group, the specimens did not receive any additions; for the test group, different concentrations of nano-ZrO2/GFs at 5% of the PMMA polymer were added. The concentrations of nano-ZrO2/GFs were as follows: 5%–0%, 4%–1%, 3%–2%, 2.5%–2.5%, 2%–3%, 1%–4%, and 0%–5%. The flexural strength was measured using the three-point bending test. The impact strength was measured using the Charpy impact test. Results were tabulated and analyzed using one-way analysis of variance (ANOVA) and the Tukey–Kramer multiple comparison test (p ≤ 0.05). The flexural and impact strengths of PMMA-nano-ZrO2 + GF composites were significantly improved when compared with those of pure PMMA (p < 0.05). The maximum flexural strength (94.05 ± 6.95 MPa) and impact strength (3.89 ± 0.46 kJ/m2) were obtained with PMMA (2.5%)/nano-ZrO2 + 2.5% GF mixtures and could be used for removable prosthesis fabrication.