Objective To explore the effects of nano-zinc oxide on the antibacterial performance and mechanical properties of heat-curing denture base resin. Methods In this study, heat-curing denture base resin was taken as the research subject, and nano-zinc oxide was used as the modified filler. Gradient groups were set for antibacterial tests with mass fractions of nano-zinc oxide at 0% (blank control), 0.1%, 0.2%, 0.3%, 0.4% and 0.5%. Gradient groups for mechanical tests were set at 0% (blank control), 1%, 3% and 5%. Standard resin specimens were prepared via unified thermal curing process, with six parallel specimens in each group. The minimum bactericidal concentration (MBC) of gradient nano-zinc oxide suspensions was determined. Streptococcus mutans was cultured in vitro, and antibacterial experiments were performed on modified resin specimens to calculate the antibacterial rate of each group. The flexural strength of resin specimens with different filler contents was tested by a three-point bending test using a universal testing machine, and the changes in antibacterial and mechanical properties of the modified resin were compared and analyzed. Results The minimum bactericidal concentration of nano-zinc oxide against Streptococcus mutans was 0.3125 mg/ml. The antibacterial rate of resin increased gradually with the rising addition of nano-zinc oxide, reaching 100% at the mass fraction of 0.4% and entering a saturated plateau stage. The flexural strength of resin increased first and then decreased with the increase of filler content. The 3% group achieved the peak flexural strength of (126.86±7.07)MPa, which was significantly higher than (96.38±8.75)MPa of the blank control group (P <0.01). The strength of the 5% group decreased but was still better than that of the blank control group (P <0.05). Conclusion Nano-zinc oxide can significantly enhance the resistance of heat-curing denture base resin against Streptococcus mutans, and complete antibacterial effect can be achieved at a mass fraction of 0.4%. The addition of 3% nano-zinc oxide maximizes the flexural strength of resin, while excessive filler destroys the continuity of the resin matrix and reduces mechanical properties. Clinically, appropriate addition ratios can be selected according to restorative needs to optimize the antibacterial durability, mechanical performance and aesthetic performance of dentures.