Abstract: Although macrophage-mediated inflammatory responses and foam cell formation play pivotal roles in atherosclerosis (AS), research on natural compounds targeting the CD40-CD40L signaling pathway remains limited. This study aims to elucidate the molecular mechanism by which Corilagin inhibits macrophage activation through this pathway, thereby providing novel therapeutic targets for natural product-based AS treatment. In vitro experiments utilizing an LPS-induced RAW264.7 macrophage injury model demonstrated that Corilagin (IC₅₀ = 41.25 μmol/L) significantly suppressed cell proliferation and foam cell formation (P < 0.05), as determined by CCK-8 assay, Oil Red O staining, and cholesterol quantification. Mechanistic investigations revealed that Corilagin downregulated key components of the CD40-CD40L-TRAF-1 pathway (at both mRNA and protein levels) and pro-inflammatory cytokines (IL-6, IFN-γ), while upregulating iNOS expression (P < 0.05). The essential role of this pathway was further confirmed through co-treatment with a specific CD40-CD40L inhibitor (DRI-C21045). This study provides the first evidence that Corilagin attenuates macrophage activation and lipid accumulation by modulating the CD40-CD40L-TRAF-1 axis, offering new insights into the potential application of natural products for AS intervention.