This study aimed to develop drug delivery system of doxycycline‐loaded polycaprolactone (PCL) microspheres. The investigated microsphere formulation can be considered for local application in bone infections and degenerative joint diseases, which generally require long‐term treatments via systemic drugs. PCL‐14 kDa and 65 kDa were used in microsphere preparation. Before release, the microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, and X‐ray photoelectron spectroscopy. The mean particle size of microspheres was in the range of 74–122 µm and their drug loadings ranged between 10 and 30%. In vitro release profiles were described using the Higuchi and the Korsmeyer–Peppas equations. Diffusion model was applied to experimental data for estimating diffusion coefficients of microspheres; calculated as between 4.5 × 10−10 and 9.5 × 10−10 cm2/s. Although long‐term release from microspheres of PCL‐14 kDa obeyed diffusion model, PCL‐65 kDa microspheres showed this tendency only for some period. Modeling studies showed that the drug release mechanism was mainly dependent on loading and molecular weight differences. Release behavior of PCL‐65 kDa microspheres, however, might be better represented by derivation of a different equation to model for the total release period. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41768