A novel biocompatible and hydrophobic drug-loaded cellulose triacetate (CTA) aerogel was prepared using supercritical antisolvent process for drug delivery system. In this work, it was investigated the influences of the size and the distribution of drug in the CTA aerogels on the drug release property. All CTA aerogels showed high loading capacity with 3D irregularly shaped nanoscale pores. The CTA/paracetamol (PA) aerogels had low volume shrinkage and high drug content from 19.8% to 61.8% (w/w), with high specific surface area and porosity. The distribution of drug was higher close to the surface in all CTA/PA aerogel. The smaller particles and more uniform distribution of drug caused slower dissolution of drug from the hydrophobic CTA aerogel. The wellness of Ritger-Peppas model fitting suggests that release of paracetamol from CTA aerogels follows Fickian diffusion. The high drug uptake and slow release rate from CTA aerogel shows the high potential for pharmaceutical applications.