To assess the effect of hygiene protocols and time on the physical–mechanical properties and colony-forming units (CFU) of Candida albicans, Staphylococcus aureus, and Streptococcus mutans on 3D-printed denture resins (SmartPrint and Yller) with extrinsic pigmentation compared to conventional resin (CR). The protocols were evaluated: brushing (B), brushing and immersion in water (W), 0.25% sodium hypochlorite (SH), and 0.15% triclosan (T), simulating 0, 1, 3, and 5 years. The data were analyzed by ANOVA with repeated measurements, ANOVA (Three-way) and Tukey’s post-test, generalized linear model with Bonferroni adjustment, and ANOVA (Two-way) and Tukey’s post-test (α = 0.05). The protocols influenced color (p = 0.036) and Knoop hardness (p < 0.001). Surface roughness was influenced by protocols/resin (p < 0.001) and time/resin (p = 0.001), and flexural strength by time/protocols (p = 0.014). C. albicans showed interactions with all factors (p = 0.033). Staphylococcus aureus was affected by protocols (p < 0.001). Streptococcus mutans exhibited no count for SH and T (p < 0.001). Yller resin showed more color changes. The 3D-printed resins displayed lower microhardness, increased roughness, and decreased flexural strength compared to CR with all protocols in a simulated period of 5 years. The indication of printed resins should be restricted to less than 3 years.