To explore the effect of nanofiller–polymer interaction on the drug release behaviour from a monolithic membrane prepared by Ca-deficient hydroxyapatite (CDHA)/chitosan nanocomposite, release kinetics was investigated in terms of different synthetic processes, i.e. in situ and ex situ routes, and various amounts of CDHA. It was found that a higher value of diffusion exponent (n) was obtained for the membranes in situ synthesized compared with those ex situ prepared. In addition, the n value of the membranes in situ synthesized increased with increasing CDHA amount, which remained in the range below 10wt.%. However, as CDHA content exceeded 30%, the n value remained constant. It indicates that the drug diffusion mechanism is altered by the CDHA–chitosan interaction which is strongly influenced by both the synthesis process and the concentration of the CDHA nanofiller in the membrane. On the other hand, a lower permeability (P) value of the membranes was observed for those prepared via the in situ process. Furthermore, P value decreased and increased with increasing CDHA amount in the range below and above 10wt.%, respectively. It demonstrates that CDHA nanofillers act either diffusion barrier or diffusion enhancer for the CDHA/chitosan membranes, which is determined by the concentration of CDHA nanofiller and the synthesis route of nanocomposite.