Intimal hyperplasia (IH) occurs in vascular bypass grafts and is responsible for their failure. This study aimed to encapsulate high payload of atorvastatin (ATV) to efficiently prevent IH, and to evaluate its activity towards synthetic smooth muscle cells (SMC), implicated in IH progression. Poly (lactic-co-glycolic acid) microparticles (MPs) were formulated by spray-drying with three nominal drug loadings: 10, 20 and 30% w/w. We have measured the particle drug load and studied the release of ATV for 90 days with U-HPLC analysis. Scanning electron microscopy, as well as Energy Dispersive X-ray Spectroscopy were used to discuss the differences in the release profiles from the MPs with different drug loadings. The MPs were sterilized by γ-rays and were incubated with synthetic SMC, obtained from pig coronary arteries. We evaluated the impact of ATV release on cell migration, proliferation with flow cytometry, and performed real-time polymerase chain reaction to determine the effect on the dedifferentiation markers. The obtained particles had high drug loads with 76–85% encapsulation efficiencies. Sustained drug release for 90 days was achieved with 10 and 20% ATV-loaded MPs. The comparison of the MPs before and after γ-ray sterilization showed no major influence of the treatment on particle morphology, size or polymer molecular weight, indicating their potential for further use in vitro and in vivo. The ATV-loaded MPs could reverse the synthetic phenotype of SMCs and attenuated their migratory and proliferative capacities.