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To assess the effect of hygiene protocols and time on the physical–mechanical properties and colony-forming units (CFU) of <i>Candida albicans</i>, <i>Staphylococcus aureus</i>, and <i>Streptococcus mutans</i> 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 (<i>p</i> = 0.036) and Knoop hardness (<i>p</i> < 0.001). Surface roughness was influenced by protocols/resin (<i>p</i> < 0.001) and time/resin (<i>p</i> = 0.001), and flexural strength by time/protocols (<i>p</i> = 0.014). <i>C. albicans</i> showed interactions with all factors (<i>p</i> = 0.033). <i>Staphylococcus aureus</i> was affected by protocols (<i>p</i> < 0.001). <i>Streptococcus mutans</i> exhibited no count for SH and T (<i>p</i> < 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.