Objective To investigate the anti-inflammatory effects and safety of decursin in atherosclerosis, and to verify its regulatory role in macrophage inflammatory responses. Methods An atherosclerosis model was established using apolipoprotein E deficient (ApoE^-/-) male mice fed a high-fat diet. RAW 264.7 macrophages were stimulated with oxidized low-density lipoprotein (oxLDL) to induce foam cell formation. Oil Red O (ORO) staining was employed to measure the reduction in aortic plaque area. Western blotting was performed to detect the phosphorylation levels of nuclear factor-κB (NF-κB). Inflammatory cytokine levels in serum and cell supernatants were analyzed using inflammatory cytokine arrays. Systemic toxicity of decursin was assessed by hematoxylin-eosin (HE) staining. Results Decursin significantly reduced aortic plaque area and inhibited the excessive activation of NF-κB in oxLDL-stimulated macrophages. It downregulated the expression of pro-inflammatory cytokines [interleukin (IL)-2 and interferon (IFN)-γ] while upregulating anti-inflammatory cytokines (IL-4 and IL-10). Furthermore, in the ApoE^-/- mouse model, decursin similarly significantly lowered serum levels of pro-inflammatory cytokines and elevated those of anti-inflammatory cytokines. HE staining results showed that decursin caused no obvious pathological damage to major organs.Conclusions Decursin exerts significant anti-inflammatory effects by regulating macrophage inflammatory responses, alleviates atherosclerotic lesions, and demonstrates a high safety profile, suggesting its potential as a therapeutic agent for atherosclerosis.