The study of natural materials inspires sustainable innovations, with biomimetics excelling in surface modification. Polydopamine (PDA) offers a promising approach for modifying cellulose nanocrystals (CNC), enhancing their compatibility with hydrophobic polymers by improving interfacial adhesion. In this work, the modification of CNC with PDA (CNC@PDA) significantly enhanced the compatibility between the nanocargoes and the cellulose acetate (CA) matrix. The CNC@PDA complex formation was suggested through a combination of FTIR analysis, particle size distribution measurements and ζ-potential analysis. However, the exact mechanism behind dopamine polymerization on the surface of CNC remains a subject of ongoing debate among researchers due to its complexity. This study hypothesized the formation of modified CNC through this process. Furthermore, this study provided a satisfactory investigation of the antimicrobial activity of CNC@PDA in response to bacterial strains (E. coli, P. aeruginosa, S. aureus and L. plantarum) in view of the hypothesis of the possible generation of reactive oxygen species (ROS). Additionally, the incorporation of CNC@PDA CA films was analyzed to assess its effect as a mechanical reinforcement agent. The results showed an improvement in mechanical properties, with the 1% CNC@PDA film exhibiting the best balance between tensile strength and flexibility.