Cortex Moutan (Paeonia suffruticosa Andrews, Ranunculaceae) has several uses in traditional medicine, such as analgesic, antipyretic, and anti-inflammatory applications and use in the prevention of thromboembolic diseases. Paeonol, a main active component in Cortex Moutan, possesses various pharmacological activities, particularly an anti-atherosclerosis effect. However, so far there have been no reports evaluating the anti-inflammatory action of paeonol in atherosclerosis therapy. The purpose of this study was to investigate the association of the therapeutic effect of paeonol on atherosclerotic rabbits with its anti-inflammatory action. The atherosclerotic model was developed in 24 rabbits fed a high-fat diet for 12 weeks. Twelve rabbits on the high-fat diet then were administered with paeonol (p.o) for a subsequent 6 weeks at the doses of 75 mg/kg and 150 mg/kg. Histological analysis showed significant improvement in atherosclerosis plaque in the paeonol groups. Moreover, the blood levels of TNF-α, IL-1β, and CRP and the translocation of NF-κB to the nucleus were significantly suppressed in paeonol groups, as was the inhibition of lipid peroxidation. In conclusion, these findings suggest that the anti-inflammatory action of paeonol may contribute to its anti-atherosclerosis effect.