Diffusion of drug molecules in polymer materials is of great importance in controlled drug release, and the investigation of the mechanism of drug release from the polymer matrix would help us to understand the release behavior of the controlled release system. In this work, molecular dynamics simulations were employed to investigate the diffusion mechanisms of penetrant molecules with different sizes in poly(lactic acid-co-ethylene glycol) (PLA-PEG). The size effect on the diffusion mechanism of penetrant molecules in polymer matrixes was discussed in detail. A competition mechanism in a two-step diffusion process-(1) motion within the cavities (free volumes), and (2) jumps between cavities or movement of the cavity itself originated from the wriggling of the polymer chains-was observed, and the contributions of these two factors to the diffusion coefficient were successfully separated. With the medium volume of penetrant molecules (e.g., benzene), a competition between these two steps was observed. Step (2) controlled the diffusion when penetrant molecules became bigger.