ABSTRACTPolymers confined in the nanoscale exhibit various unusual properties that are not seen in bulk polymers. Here, the effect of nanoscale confinement on the drug release properties of polymer nanofibers is investigated by analyzing the molecular mobility and drug release kinetics of cellulose acetate/sulindac nanofibers (CNs). It is observed that the activation energy, Ea, for molecular motion of both the main chain and side chain tended to increase as the diameter of the CNs decreased from 850 to 260 nm. The increased Ea indicates that the chains confined in ultrathin CNs are closely packed, resulting in a low molecular mobility. With decreasing diameter from 620 to 260 nm, the diffusion coefficient of drug is significantly decreased from 85.3 to 10.3 nm2 min−1. Such correlation between Ea and drug diffusion rate indicates that the confinement‐induced suppression of the molecular motion could significantly affect the drug release properties of polymer nanofibers. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47863.