Atherosclerosis is regarded as a chronic inflammatory disease which immune response is regulated by multiple factors. Pseudorlaric acid D (PLAD) is the main bioactive component of Pseudolarix kaempferi Gorden, but little of its property has been found in the literature. We aimed to investigate the anti-inflammatory activity and the underlying mechanisms of PLAD on atherosclerosis. In this study, atherosclerosis model was established by feeding with a high-fat diet in ApoE^−/− mice. PLAD was administered intragastrically at a dose of 5 mg/kg for four weeks. We found that PLAD could significantly improve the lipid metabolism and decrease atherosclerotic lesion areas as well as mitigate atherosclerotic changes on vessel walls. Besides, PLAD could markedly inhibit the inflammatory response by down-regulating the levels of Ly6C^hi monocytes and NETs, and restraining NETs formation. The expression of pro-inflammatory cytokines IL-1β and IL-18 was also evidently reduced by PLAD. These results indicated that modulating the activation and recruitment of Ly6C^hi monocytes and NETs could be the potential anti-inflammatory mechanisms of PLAD on atherosclerosis. PLAD might be a promising therapeutic strategy for the treatment of atherosclerosis and inflammation-related diseases.