Talc is one of the most commonly used antiadherents in the coating film. However, the mechanism of influence of talc on drug release has yet to be fully understood. In this study, metoprolol tartrate (MT)-loaded Eudragit NE 30 D-coated sustained-release (SR) pellets were prepared using talc as an antiadherent in the layering and coating processes. Talc significantly reduced the stickiness of the layered or coated substrates, thus enhancing the process smoothness. Moreover, the incorporation of talc into the coating film significantly affected drug release. The water vapor permeability and drug permeability of free films increased as the concentration of talc increased. Importantly, talc had a dynamic effect on the drug release. The drug release rate of the pellets in the initial stage (within 2 h) increased with increasing talc concentrations, which exceeded the critical pigment volume concentration resulted in leaks formation in the coated film. However, subsequent swelling of the membrane and expansion of the copolymer network eliminated the influence of talc and the drug release was then controlled by the polymeric membrane. These results suggest that talc contributed to the reduction of the sticking of layered or coated substrates, and facilitated the manufacturing process and drug release properties.