Overuse of antibiotic drugs usually leads to the further development of resistance to targeted bacteria. In this context, a controlled release system could be a solution to achieve higher drug efficiency without overdosing and drug resistance. In this work, nanocomposite films based on chitosan (CHI) reinforced with cellulose anofibrils(CNF) for antibiotic release were prepared and characterized. Several nanocomposite films containing vancomycin hydrochloride and different amounts of CNF (5, 10, and 20 wt%) were prepared by the solventcasting method. Spectroscopic (FTIR), thermal (TG), morphological (SEM), mechanical, and swelling analyses of the films were performed to study the effect of nanofibers content on the nanocomposite properties. A good dispersion of CNF and the model drug was observed in the CHI matrix. FTIR spectroscopy confirmed the interaction between the film components (CNF and CHI). Film swelling capacity decreased with an increase of CNF content in the film formulation, whereas stiffness and tensile strength of the film increased. In addition, vancomycin release at pH = 7.4 was studied, and it was observed that controlled slower release could be achieved by tuning the CNF content in the chitosan film. The results confirm that these films could be useful for pharmaceutical purposes where the controlled release of drugs is required.