Cellulose nanocrystals (CNCs) are cellulose-derived nanomaterials that can be easily obtained, e.g., from vegetable waste produced by circular economies. They show promising antimicrobial activity and an absence of side effects and toxicity. This study investigated the ability of CNCs to reduce microbial adherence and biofilm formation using in vitro microbiological models reproducing the oral environment. Microbial adherence by microbial strains of oral interest, Streptococcus mutans and Candida albicans, was evaluated on the surfaces of salivary pellicle-coated enamel disks in the presence of different aqueous solutions of CNCs. The anti-biofilm activity of the same CNC solutions was tested against S. mutans and an oral microcosm model based on mixed plaque inoculum using a continuous-flow bioreactor. Results showed the excellent anti-adherent activity of the CNCs against the tested strains from the lowest concentration tested (0.032 wt. %, p < 0.001). Such activity was significantly higher against S. mutans than against C. albicans (p < 0.01), suggesting a selective anti-adherent activity against pathogenic strains. At the same time, there was a minimal, albeit significant, anti-biofilm activity (0.5 and 4 wt. % CNC solution for S. mutans and oral microcosm, respectively, p = 0.01). This makes CNCs particularly interesting as anticaries agents, encouraging their use in the oral field.